Front. Mol. Neurosci. Frontiers in Molecular Neuroscience Front. Mol. Neurosci. 1662-5099 Frontiers Media S.A. 10.3389/fnmol.2025.1635119 Neuroscience Mini Review LncRNA-driven programmed cell death networks: new therapeutic targets for neurological disorders Xiong Zihong 1 2 Sun Chao 1 3 Huang Shiyong 1 * 1Department of Pediatric Intensive Care Unit, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China 2Department of Pediatrics, Chongzhou Health Center for Women and Children, Chongzhou, China 3Department of Pediatrics, Southwest Medical University, Luzhou, China

Edited by: Robert John Vandenberg, The University of Sydney, Australia

Reviewed by: Paulina Carriba, Centre for Genomic Regulation (CRG), Spain

 *Correspondence: Shiyong Huang, hsy_chengdupicu@126.com 24 07 2025 2025 18 1635119 26 05 2025 07 07 2025 Copyright © 2025 Xiong, Sun and Huang. 2025 Xiong, Sun and Huang

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Neural cell death is a critical pathological mechanism underlying the development and progression of central nervous system (CNS) diseases, where programmed cell death (PCD) pathways serve as critical regulatory hubs. In addition to classical apoptosis and autophagy, emerging PCD modalities including necroptosis, pyroptosis, ferroptosis, and cuproptosis exhibit distinct activation patterns in different neurological diseases. Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators of these PCD processes through multiple molecular strategies by modulating chromatin accessibility, assembling signaling complexes, and regulating post-transcriptional processes. These regulatory interactions vary by cellular location and disease stage, influencing cell fate through membrane receptors, kinase cascades, and nuclear transcriptional programs. In various CNS pathologies, specific lncRNAs display dual regulatory capacities—promoting neuronal death by amplifying cytotoxic signals or conferring neuroprotection by inhibiting these pathways. The dynamic lncRNA-PCD interactions offer therapeutic potential through targeted modulation of lncRNA networks to control neuronal survival. Future investigations should prioritize systematic mapping of context-specific lncRNA regulatory networks governing distinct PCD modalities, concurrently advancing spatial epigenomic editing technologies for precise manipulation of these regulatory circuits. Understanding these molecular interactions better will help identify therapeutic targets and guide CNS drug development.

 long non-coding RNA central nervous system disease neural cells programmed cell death cell death section-at-acceptance Molecular Signaling and Pathways 1 Introduction

Long non-coding RNAs (lncRNAs), defined as longer than 200 nucleotidest non-protein-coding transcripts (Nitsche and Stadler, 2017), have transitioned from being mischaracterized as transcriptional noise to emerging as master regulators of gene expression through diverse mechanisms including transcriptional modulation (histone modification, cofactor recruitment), RNA processing (alternative splicing), and post-translational regulation—notably functioning as endogenous RNA sponges within competing endogenous RNA (ceRNA) networks (Khoshnam et al., 2024; Kitagawa et al., 2013; Ruffo et al., 2023; Wu et al., 2021; Yang et al., 2023). Their region-specifically enriched expression in murine hippocampal, cortical, and thalamic structures (Kadakkuzha et al., 2015) and zebrafish CNS (brain/spinal cord) (Kaushik et al., 2013) demonstrates conserved regulation across vertebrate neural systems, underpinning roles in coordinating neural cell proliferation, differentiation, and programmed death (Ghafouri-Fard et al., 2022; Herman et al., 2022; Kleaveland et al., 2018; Wu and Kuo, 2020). This review synthesizes lncRNA-mediated regulation of neural programmed cell death (PCD) by integrating three fundamental dimensions: (1) functional convergence and divergence across apoptosis, autophagy, pyroptosis, ferroptosis, and cuproptosis pathways; (2) shared mechanistic principles spanning ceRNA networks and epigenetic reprogramming; and (3) context-specific dysregulation in neurodegeneration and neurotrauma, thereby addressing the identified knowledge gap in lncRNA-PCD interactomes within the nervous system.

 2 LncRNA-mediated programmed neural cell death in central nervous system diseases 2.1 Apoptosis

Apoptosis—an evolutionarily conserved cell death mechanism mediating tissue homeostasis—executes through cytoplasmic shrinkage, nuclear fragmentation, and apoptotic body formation via two core pathways: (1) The mitochondrial pathway, where oxidative stress induces Bax/Bak-mediated mitochondrial pore formation, cytochrome c release, and apoptosome assembly (Apaf-1/pro-caspase-9), culminating in caspase-9 autoactivation and downstream caspase-3/7 proteolysis; (2) The death receptor pathway, initiated by extracellular ligands (FasL/TNF-ɑ) that trimerize receptors to recruit FADD and pro-caspase-8, forming the DISK complex for caspase-8 dimerization-driven autocleavage (Amgalan et al., 2017; Fernández et al., 2015; Riley and Bock, 2022; Schwarzer et al., 2020; Van Opdenbosch and Lamkanfi, 2019). Crucially, while dysregulation of these pathways drives neurodegeneration in cerebral ischemia and chronic disorders, lncRNAs’ regulatory roles in modulating key molecular switches—such as Bax activation thresholds, apoptosome stoichiometry, or DISK assembly kinetics—remain underexplored in neural contexts.

Emerging evidence establishes specific lncRNAs as critical coordinators of cell fate across pathologies. In solid tumors, plasmacytoma variant translocation 1 (PVT1) and p21-associated lncRNA exemplify dual-function regulators orchestrating cellular apoptosis while mediating therapeutic resistance through apoptotic threshold modulation (Ferrer and Dimitrova, 2024; He et al., 2018; Li et al., 2022). In ischemic stroke, MEG3 orchestrates bimodal apoptotic control via hnRNPA1 sequestration to induce Sirt2-dependent mitochondrial dysfunction (Yao et al., 2024), concurrently sequestering cytoplasmic miR-21 to elevate PDCD4 and activate caspase-3 (Yan et al., 2017). The lncRNA KCNQ1OT1 exerts neurotoxic effects by competitively binding miR-296-5p, upregulating Bax expression and enhancing mitochondrial cytochrome c release (Li et al., 2020), while SNHG14 attenuates neuronal injury via miR-98-5p sponging to upregulate BCL2L13 in neuro-2a cells (Zhang et al., 2022). Functional heterogeneity is evident in NEAT1: Global suppression dysregulates synaptic plasticity (Li and Wang, 2023), whereas pharmacological induction by bexarotene elevates NEAT1 to attenuate Pidd1-caspase-2 signaling in traumatic brain injury (Zhong et al., 2017). Neuroprotective mechanisms include N1LR-mediated inhibition of p53 phosphorylation at Ser15 (Wu et al., 2017), and TUG1 promoting neuronal apoptosis through miR-9 sponging and Bcl2l11 upregulation (Chen et al., 2017). The ZFAS1 neuroprotective axis demonstrates miR-582 sequestration to upregulate NOS3 expression (Zhang and Zhang, 2020), while Rian attenuates apoptosis via miR-144-3p/GATA3 signaling (Yao et al., 2020) and Oprm1 reduces cell death through miR-155/GATA3 signaling (Jing et al., 2019). Critically, comparative profiling reveals divergent targeting of death pathways: stroke-associated lncRNAs (MEG3, KCNQ1OT1) converge on mitochondrial apoptosis, whereas neuroprotective lncRNAs (NEAT1, ZFAS1, N1LR) modulate caspase-dependent survival. These systematically cataloged mechanisms establish lncRNAs as hierarchically organized master regulators of neuronal fate (Table 1).

Long non-coding RNAs (LncRNA)-driven neuronal apoptosis: targets and mechanisms.

LncRNA Disease model Expression Molecular axis Functional outcome References
MEG3 Ischemic stroke ↑ MEG3↑→ miR-21↓→ PDCD4↑ MEG3↑→ hnRNPA1↓→ Sirt2↓ Drives neuronal death via PDCD4 signaling and mitochondrial dysfunction Yan et al., 2017; Yao et al., 2024
KCNQ1OT1 Neuroblastoma ↑ KCNQ1OT1↑→ miR-296-5p↓→ Bax↑ Promotes apoptosis via Bax activation Li et al., 2020
SNHG14 OGD/R neuro-2a model ↑ SNHG14↑→ miR-98-5p↓→ BCL2L13↑ Reduces apoptosis in neuronal cells Zhang et al., 2022
NEAT1 Traumatic brain injury ↑ Bexarotene↑→ NEAT1↑→ PIDD1↓→ Caspase-2↓ Bexarotene-induced neuroprotection Li and Wang, 2023; Zhong et al., 2017
N1LR Ischemic stroke ↓ N1LR overexpression → p53-Ser15 phosphorylation↓→ PUMA↓ Neuroprotection via p53 inhibition in neurons Wu et al., 2017
TUG1 OGD-induced neurons ↑ TUG1↑→ miR-9↓→ Bcl2l11↑ Promotes neuronal apoptosis via Bim activation Chen et al., 2017
ZFAS1 Cerebral I/R injury ↑ ZFAS1↑→ miR-582↓→ NOS3↑ Neuroprotection via NOS3-mediated apoptosis inhibition Zhang and Zhang, 2020

OGD/R, oxygen-glucose deprivation/reperfusion; I/R, ischemia/reperfusion; PDCD4, programmed cell death 4; hnRNPA1, heterogeneous nuclear ribonucleoprotein A1; Sirt2, sirtuin 2; Bax, BCL2-associated X protein; BCL2L13, BCL2 like 13; PIDD1, p53-induced death domain protein 1; PUMA, p53 upregulated modulator of apoptosis; Bim, BCL2-like 11 (Bcl2l11); NOS3, nitric oxide synthase 3;↑, upregulation; ↓, downregulation.

 2.2 Autophagy

Autophagy—an evolutionarily conserved lysosomal degradation system comprising three mechanistically distinct forms: microautophagy, macroautophagy, and chaperone-mediated autophagy (Dikic and Elazar, 2018)—facilitates clearance of damaged organelles and protein aggregates through double-membrane autophagosome formation. This catabolic process serves dual homeostatic and stress-responsive functions against oxidative injury, ischemia, and infection (Bernard et al., 2015; Lei and Klionsky, 2021; Mizushima et al., 2008; Siddiqui et al., 2015), governed by the PI3K-AKT1-mTOR signaling axis and core regulators (mTOR, Beclin-1, ATGs, AMPK). Crucially, while macroautophagy plays a defined pathogenic role in neurodegeneration through mediating aberrant protein clearance failure (Nixon, 2013), lncRNAs’ regulatory involvement in modulating these molecular components—particularly through PI3K-AKT1-mTOR pathway interaction—remains uncharacterized in neurological contexts.

Dysfunctional autophagy drives proteinopathic neurodegeneration across CNS disorders: Glial autophagic failure exacerbates amyloidopathy and tauopathy in Alzheimer’s disease (Litwiniuk et al., 2023), while mutant ataxin-3-induced autophagic flux disruption in Machado-Joseph disease (SCA3) is mitigated by Beclin-1 enhancement (Nascimento-Ferreira et al., 2011). LncRNAs regulate neuronal homeostasis via competitive endogenous RNA (ceRNA) mechanisms, exemplified by H19’s context-dependent duality: In adult cerebral ischemia, it sequesters miR-29a to activate ERK1/2-dependent autophagy via DUSP5 suppression, exacerbating injury (Wang et al., 2017); in neonatal hypoxic-ischemic encephalopathy, it sponges miR-29b to promote AKT3-mediated mTOR inhibition, reducing neuronal apoptosis (Zhu et al., 2022). LncRNA-driven PCD networks in Parkinson’s disease demonstrate complementary control: Downregulated SNHG1 activates autophagy via miR-221/222-p27-mTOR signaling (Qian et al., 2019), while BDNF-AS upregulation promotes autophagic apoptosis through miR-125b-5p suppression (Fan et al., 2020), concurrent with NEAT1 stabilizing PINK1 to reinforce autophagic clearance (Yan et al., 2018). This functional dichotomy—SNHG1 impeding neuronal death versus BDNF-AS accelerating degeneration—epitomizes context-dependent lncRNA governance within MPTP-induced Parkinsonian models. In cerebral ischemia, C2dat2 sequesters miR-30d-5p to activate DDIT4-dependent autophagy and apoptosis, potentiating reperfusion injury (Xu et al., 2021), while SNHG12 silencing amplifies mesenchymal stem cell efficacy by activating PI3K/AKT/mTOR signaling (Li et al., 2019). MALAT1 orchestrates microvascular protection through validated complementary routes: Sequestering miR-200c-3p in oxygen-glucose deprivation to trigger SIRT1-mediated survival (Wang et al., 2019), and sponging miR-26b during hypoxia-reoxygenation to enhance ULK2-dependent cytoprotection (Li et al., 2017). Therapeutically, Lethe enhances autophagic clearance in cortical neurons to mitigate sepsis-induced brain injury (Mai et al., 2019), while Cox2 knockdown suppresses NLRP3 inflammasome activation via coordinated autophagy regulation (Xue et al., 2019). This plasticity—H19’s duality and MALAT1’s microenvironment-specific outcomes—confirms lncRNAs as master integrators of programmed cell death. These programmable circuits provide transformative therapeutic strategies, with regulatory hierarchies mapped in Table 2.

Long non-coding RNAs (LncRNA)-driven neuronal autophagy: targets and mechanisms.

LncRNA Disease model Expression Molecular axis Functional outcome References
H19 Cerebral ischemia/reperfusion ↑ H19↑→ mTOR↓→ autophagy↑ Induces neuronal injury via mTOR-dependent autophagy Wang et al., 2017
H19 Neonatal HIE ↑ H19↑→ miR-29b↓→ PI3K/AKT↑→ mTOR↑ Reduces neuroprotective autophagy via mTOR activation Zhu et al., 2022
SNHG1 Parkinson’s disease MPTP-treated SH-SY5Y ↓ SNHG1↓→ miR-221↓/miR-222↓→ p27↑→ mTOR↓ Enhances neuroprotective autophagy and prevents cell death Qian et al., 2019
BDNF-AS MPTP-induced Parkinson’s disease ↓ BDNF-AS↓→ miR-125b-5p↑→ BCL2↓→ ULK1↑ Enhances neuroprotective autophagy and promotes apoptosis Fan et al., 2020
NEAT1 MPTP-induced Parkinson’s disease ↑ NEAT1↑→ TRIM11↑→ PARIS↓→ PINK1↑ Promotes protective mitophagy by stabilizing PINK1 protein Yan et al., 2018
C2dat2 Cerebral ischemia-reperfusion ↑ C2dat2↑→ miR-30d-5p↓→ DDIT4↑→ mTOR↓ Promotes neuronal apoptosis and autophagy via the miR-30d-5p/DDIT4/mTOR axis Xu et al., 2021
SNHG12 Cerebral ischemia/reperfusion ↑ SNHG12↓→ IGF-1↑→ PI3K/AKT/mTOR↑ Enhances MSC therapy efficacy by suppressing neuronal apoptosis and autophagy Li et al., 2019
MALAT1 OGD-treated brain microvascular endothelial cells ↑ MALAT1↑⟷ miR-200c-3p↓→ SIRT1↑ Protects against OGD injury via SIRT1-mediated pro-survival autophagy Wang et al., 2019
MALAT1 OGD/R-treated brain microvascular endothelial cells ↑ MALAT1↑→ miR-26b↓→ ULK2↑ Protects against OGD/R injury by inducing pro-survival autophagy Li et al., 2017
Lethe CLP-induced sepsis brain injury ↑ Lethe↑→ FoxO3a nuclear translocation↑→ Autophagy genes↑ Attenuates neuronal apoptosis via enhancing protective autophagy flux Mai et al., 2019
Cox2 Experimental Autoimmune Encephalomyelitis ↑ Cox2↑→ hnRNPA2B1↑→ NLRP3 inflammasome↑→ autophagy↓ Amplifies neuroinflammation by activating NLRP3 inflammasome and suppressing autophagy Xue et al., 2019

HIE, hypoxic-ischemic encephalopathy; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; OGD, oxygen-glucose deprivation; OGD/R, oxygen-glucose deprivation/reperfusion; CLP, cecal ligation and puncture; SH-SY5Y, human neuroblastoma cell line; mTOR, mechanistic target of rapamycin; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; BCL2, B-cell lymphoma 2; ULK1, unc-51 like autophagy activating kinase 1; TRIM11, tripartite motif-containing 11; PARIS, PARK2-interacting substrate; PINK1, PTEN induced kinase 1; DDIT4, DNA damage inducible transcript 4; IGF-1, insulin-like growth factor 1; MSC, mesenchymal stem cells; SIRT1, sirtuin 1; FoxO3a, forkhead box O3; NLRP3, NLR family pyrin domain containing 3; hnRNPA2B1, heterogeneous nuclear ribonucleoprotein A2/B1; ↑, upregulation; ↓, downregulation.

 2.3 Pyroptosis

Pyroptosis represents a caspase-dependent lytic cell death pathway characterized by gasdermin-mediated membrane pore formation and proinflammatory cytokine release. Its activation occurs through two distinct routes: the canonical pathway triggered by NOD-like receptor inflammasomes (NLRP3, NLRC4, AIM2, Pyrin) activating caspase-1, and the non-canonical pathway dependent on caspase-4/5/11 (Ai et al., 2024; Bai and Zhang, 2021; Huang et al., 2021; Mi et al., 2022; Paerewijck and Lamkanfi, 2022; Pang and Vince, 2023). Both pathways converge on gasdermin-D (GSDMD) proteolysis, where liberated N-terminal fragments oligomerize to form membrane pores enabling IL-1β/IL-18 maturation and secretion—culminating in inflammatory cell lysis. Crucially, regulatory lncRNAs’ roles in modulating sensor activation thresholds or GSDMD processing remain uncharacterized in neurological contexts. Aberrant pyroptosis drives neuroinflammatory pathogenesis in Alzheimer’s, ischemic stroke, epilepsy, and Parkinson’s disease through persistent cytokine dysregulation and neuronal degeneration (Christgen and Kanneganti, 2020; Lünemann et al., 2021; Yan et al., 2022), positioning this pathway as a pathological driver and therapeutic target whose lncRNA regulatory components warrant investigation.

Emerging evidence establishes lncRNAs as master regulators of pyroptotic networks through spatiotemporally precise, cell-type-specific mechanisms. In microglia, Parkinson’s-associated SNHG1 amplifies pyroptosis via the miR-7/NLRP3 axis (Cao et al., 2018; Zhou et al., 2016), spinal injury-induced F630028O10Rik hijacks TLR4/PI3K/AKT signaling to trigger inflammasome activation (Xu et al., 2020), and diabetic hyperglycemia elevates Fendrr expression to stabilize NLRC4 through HERC2-mediated anti-ubiquitination (Wang L. Q. et al., 2021). Conversely in neurons, ischemia-activated H19 drives NLRP3/NLRP6 inflammasomes via the miR-21/PDCD4 ceRNA network (Wan et al., 2020), while hypoxia-induced MEG3 assembles AIM2 inflammasomes to activate caspase-1 cascades (Liang et al., 2020). Neurovascular dysfunction involves endothelial Xist promoting NLRP3-dependent barrier disruption via pyroptotic cleavage (Guo et al., 2022). Therapeutically, hyperbaric oxygen (HBO) suppresses H19/miR-423-5p/NLRP3 in neural stem cells to alleviate pyroptosis (Ye et al., 2022), whereas protocatechuic aldehyde inhibits Xist/NLRP3 signaling to preserve vascular integrity (Guo et al., 2022)—notably, H19 concurrently initiates microglial pyroptosis propagating neuronal deat (Wan et al., 2020). Collectively, lncRNAs architect compartmentalized neuroinflammation by coordinating microglial inflammasome priming (SNHG1, F630028O10Rik, Fendrr), neuronal pyroptosis execution (H19, MEG3), and endothelial barrier disruption (Xist), establishing a multi-tiered druggable architecture mapped in Table 3.

Long non-coding RNAs (LncRNA)-driven neuronal pyroptosis: targets and mechanisms.

LncRNA Disease model Expression Regulatory axis Functional outcome References
SNHG1 Parkinson’s disease ↑ Sponges miR-7 → Activates NLRP3 Promotes microglial pyroptosis and neuroinflammation Cao et al., 2018
F630028O-10Rik Spinal cord injury ↑ Firre↑→↓miR-1231-5p →↑Col1a1 Firre↑→ TLR4↑→ PI3K/AKT↑ Initiates TLR4/PI3K/AKT-dependent microglial pyroptosis Xu et al., 2020
Fendrr Diabetic cerebral I/R injure ↑ Fendrr↑→ HERC2 binding →↓NLRC4 ubiquitination → NLRC4↑ Stabilizes NLRC4 inflammasome to drive microglial pyroptosis Wang L. Q. et al., 2021
H19 Retinal I/R injury ↑ H19↑→ miR-21↓→ PDCD4↑ H19↑→ NLRP3↑/NLRP6↓ Triggers microglial pyroptosis via NLRP3/NLRP6 inflammasome imbalance and neuronal death Wan et al., 2020
MEG3 Ischemic stroke MCAO/R model ↑ MEG3↑→ miR-485↓→ AIM2↑ Induces neuronal pyroptosis via AIM2 inflammasome activation Liang et al., 2020
Xist Ischemic stroke ↑ Xist↑→ NLRP3 inflammasome activation Drives cerebral microvascular endothelial cell pyroptosis Guo et al., 2022
H19 Ischemic stroke ↑ H19↑→↓miR-423-5p → NLRP3↑ Drives neural stem cell pyroptosis via NLRP3 inflammasome activation Ye et al., 2022

I/R, ischemia/reperfusion; MCAO/R, middle cerebral artery occlusion/reperfusion; miR, microRNA; NLRP3, NLR family pyrin domain containing 3; TLR4, Toll-like receptor 4; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; HERC2, HECT and RLD domain containing E3 ubiquitin protein ligase 2; NLRC4, NLR family CARD domain containing 4; PDCD4, programmed cell death 4; NLRP6, NLR family pyrin domain containing 6; AIM2, absent in melanoma 2; Col1a1, collagen type I alpha 1 chain; ↑,upregulation; ↓, downregulation.

 2.4 Ferroptosis

Ferroptosis—an iron-dependent necrotic process initiated by lipid peroxidation and redox-active iron accumulation (Dixon et al., 2012)—induces oxidative destruction of polyunsaturated fatty acid-rich phospholipid membranes. Its core machinery involves Fe2+-catalyzed Fenton reactions propagating oxidative damage (Jiang et al., 2021), with distinctive mitochondrial ultrastructural changes differentiating it from other death modalities (Zheng and Conrad, 2020). This regulated cell death pathway integrates four interdependent metabolic axes: glutathione-dependent redox balance (Dixon et al., 2012), systemic iron homeostasis (Yang et al., 2016), lipid/amino acid metabolism (Dixon et al., 2015), and mitochondrial dynamics (Gao et al., 2019). Although hepatocarcinoma studies demonstrate GSTZ1-mediated ferroptosis sensitization via NRF2/GPX4 axis suppression (Wang Q. et al., 2021), pathological iron dysregulation predominantly drives neurological degeneration, manifesting as post-traumatic epileptogenesis through astrocyte ferroptosis (Chen et al., 2020) and Alzheimer’s progression potentiated by Aβ-NRF2 axis collapse (Lane et al., 2021). Execution converges on three druggable effector hubs—glutathione peroxidase 4 (GPX4) inactivation enabling lipid peroxidation propagation (Yang et al., 2014), System Xc– dysfunction depleting glutathione reserves (Dixon et al., 2012), and p53-mediated iron metabolism reprogramming (Jiang et al., 2015)—that demonstrate epigenetic susceptibility in cancer models, designating them as priority nodes for lncRNA-driven control in neurodegeneration. Nevertheless, their disease-specific regulatory architecture—particularly lncRNA-calibrated iron homeostasis dynamics—remains uncharted, constituting a fundamental knowledge gap obstructing precision-targeted neurological therapeutics development.

Long non-coding RNAs emerge as critical ferroptosis regulators in neurological injury through divergent yet complementary molecular pathways. Clinical-translational evidence reveals PVT1 silencing reduces cerebral infarct volume in acute ischemic stroke models by inhibiting ferroptosis via miR-214/transferrin receptor 1 (TFR1)/tumor protein p53 (TP53) axis (Lu et al., 2020). Conversely, serum exosome-derived NEAT1 promotes cerebrovascular endothelial ferroptosis in septic encephalopathy through concurrent modulation of miR-9-5p/transferrin receptor (TFRC) iron transport and glutamic-oxaloacetic transaminase 1 (GOT1) signaling pathways (Wei et al., 2022). Complementing these, hyperglycemia-exacerbated hypoxia induces Meg3-dependent ferroptosis in brain microvascular endothelia via p53/GPX4 antioxidant defense disruption (Chen et al., 2021). Collectively, these systematically mapped relationships (Table 4) demonstrate lncRNAs orchestrate ferroptosis through three convergent mechanisms: (1) iron homeostasis regulation (PVT1/TFR1, NEAT1/TFRC), (2) antioxidant pathway disruption (Meg3/GPX4), and (3) cellular compartmental specificity (neuronal vs. endothelial targeting), highlighting their roles as tissue-contextual arbiters of iron-dependent cell death.

Long non-coding RNAs (LncRNA)-driven neuronal ferroptosis: targets and mechanisms.

LncRNA Disease model Expression Molecular axis Functional outcome References
PVT1 Acute ischemic stroke ↓ PVT1↓→↑miR-214 →↓TFR1/↓p53 Inhibits ferroptosis through miR-214-mediated suppression of TFR1/p53 Wei et al., 2022
NEAT1 SAE ↑ NEAT1↑→↓miR-9-5p →↑TFRC/↑GOT1 Exosomal NEAT1 drives ferroptosis via miR-9-5p sponging and TFRC/GOT1 axis activation Chen et al., 2021
Meg3 Diabetic perioperative stroke ↑ Meg3↑→ p53↑→↓GPX4 Mediates p53-dependent ferroptosis via GPX4 inhibition in diabetic brain ischemic damage Hitomi et al., 2008

SAE, sepsis-associated encephalopathy; TFR1, transferrin receptor 1; GPX4, glutathione peroxidase 4; TFRC, transferrin receptor; GOT1, glutamic-oxaloacetic transaminase 1; miR, microRNA;↑, upregulation; ↓, downregulation.

 2.5 Necroptosis

Necroptosis represents a caspase-independent programmed cell death pathway defined by cytoplasmic swelling, plasma membrane rupture, and inflammatory mediator release. Its molecular cascade involves hierarchical activation: RIPK1-RIPK3 interaction initiates necrosome assembly, leading to RIPK3 autophosphorylation and MLKL recruitment (Hitomi et al., 2008; Tran et al., 2024). Subsequent MLKL phosphorylation induces oligomerization and plasma membrane translocation, forming pores that disrupt ionic homeostasis—the hallmark execution event. Beyond this canonical axis, RIPK3 orchestrates alternative signaling via mitochondrial phosphatase PGAM5, which stabilizes RIPK1/MLKL while activating CAMKII isoforms and ROS cascades (Cho et al., 2009; Prasad Panda et al., 2023; Zhan et al., 2022). This cross-compartmental signaling amplifies necroptotic responses, demonstrating the pathway’s capacity for diversification beyond the core RIPK1-RIPK3-MLKL axis while retaining membrane permeabilization as the terminal effector mechanism.

Necroptosis drives neuroinflammation through cytokine release and inflammasome activation, serving as a pathogenic mechanism in multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD) (Richard and Mousa, 2022; Yuan et al., 2019). Mechanistic studies establish RIPK1-driven necroptosis as clinically relevant in neurological pathologies: In Alzheimer’s disease models, pharmacological inhibition of RIPK1 by necrostatin-1 attenuates tau hyperphosphorylation and Aβ-induced neuroinflammation while rescuing cognitive impairment in APP/PS1 mice (Yang et al., 2017). In parallel, stroke models reveal hypoxia-induced RIPK1/RIPK3/MLKL pathway activation driving neuronal damage, where necrostatin-1 intervention improves neurological recovery in ischemic and hemorrhagic stroke by blocking necroptotic signaling (Chen et al., 2018; Shen et al., 2017). Genetic ablation studies confirm RIP1/RIP3 deficiency protects against acute ischemic injury through dual suppression of necroptosis and neuroinflammation (Zhang et al., 2020), collectively establishing necroptosis inhibition as a promising therapeutic strategy for acute and chronic neurodegenerative conditions.

Notably, cancer biology reveals conserved lncRNA-mediated necroptosis regulation relevant to neurological contexts: Colon cancer studies identify a 6-lncRNA signature modulating TNF-α/NF-κB-driven necroptosis (Liu et al., 2022), gastric adenocarcinoma research shows 12 lncRNAs regulating caspase-8/FADD-mediated death (Luo et al., 2022), and lung adenocarcinoma models reveal 7 prognostic lncRNAs linked to MLKL ubiquitination (Lu et al., 2022). Critically, shared regulatory architecture emerges with identical necroptotic effectors (RIPK1, caspase-8, MLKL) in cancer and neurodegeneration (Najafov et al., 2019; Yuan et al., 2019), lncRNA bridging via cancer-associated regulators exhibiting CNS expression (PVT1 (Zhang et al., 2019), MALAT1 (Huang et al., 2023)), and therapeutic translatability of small-molecule inhibitors effective in both ischemic stroke (necrostatin-1 (Deng et al., 2019)) and cancer. These findings establish lncRNAs as evolutionarily conserved necroptosis modulators whose mechanistic elucidation in oncology provides direct insights for developing targeted neurotherapeutics.

 2.6 Cuproptosis

Cuproptosis—a copper-dependent cell death pathway mediated by mitochondrial proteostasis collapse via copper binding to lipoylated enzymes (e.g., dihydrolipoamide S-acetyltransferase, DLAT)—involves oligomerization of lipoylated proteins and iron-sulfur cluster degradation, culminating in membrane damage via proteotoxic mechanisms (Deng et al., 2024; Tsvetkov et al., 2022). Dysregulated cuproptosis contributes to pathological manifestations in specific oncological contexts. In malignancies, dysregulation of ATP7A/B transporters mediates chemotherapy resistance, as evidenced by established prognostic models: ATP7B downregulation correlates with platinum resistance in lung cancer, while ATP7A features in cuproptosis-related gene signatures for hepatocellular carcinoma clinical stratification (Jawed and Bhatti, 2024; Shao et al., 2023). Meanwhile, in Alzheimer’s pathology, nitration modifications of β-amyloid peptides attenuate copper-mediated toxicity by inhibiting copper binding, with these copper-amyloid complexes established as neurotoxic mediators (Zhao et al., 2019). Elucidating CNS-specific cuproptosis mechanisms may reveal multipronged therapeutic opportunities, including copper-chelating agents modulating copper homeostasis (Jiang et al., 2022), metabolic modulators targeting copper-associated pathways (Gao and Zhang, 2023; Kong and Sun, 2023), and exploratory lncRNA-based interventions guided by hepatic malignancy-identified cuproptosis regulatory signatures (Mao et al., 2023). This mechanistic understanding facilitates neuroprotective intervention development for neurological disorders.

Cuproptosis signatures demonstrate significant translational potential in neuro-oncology. Studies by Zhu et al. (2024) develop an 18-gene cluster predicting low-grade glioma (LGG) survival and immunotherapy response, while subsequent research establishes lncRNA-based prognostic models incorporating 9–10 cuproptosis-associated transcripts—including functional regulators like LEF1-AS1 that suppress glioma proliferation and invasion (Chen et al., 2023; Jin et al., 2023; Wang et al., 2022). Bioinformatic analyses of Alzheimer’s datasets reveal dysregulated cuproptosis-associated genes (MTF1, NFE2L2, GLS) and lncRNAs (LY86-AS1, MIR7-3HG) (Zeng et al., 2024). These shared molecular perturbations suggest potential conservation of copper-dependent death pathways across CNS disorders, though mechanistic validation in other neuropathologies remains required. The convergence of cuproptosis-associated signatures in neuropathologies—spanning oncogenesis to proteinopathy—highlights its role as a fundamental cell death mechanism whose tissue-specific regulatory networks require prioritized validation in human neuronal models.

 3 Conclusion

Long non-coding RNAs critically coordinate neural cell death in neurological disorders through multimodal regulatory networks, concurrently modulating caspase-dependent apoptosis and non-apoptotic pathways—including ferroptosis, necroptosis, and cuproptosis—via distinct molecular interactions. Persistent knowledge gaps remain regarding PCD crosstalk (e.g., apoptosis-necroptosis interplay) and context-dependent hierarchical control in CNS pathophysiology (Bertheloot et al., 2021; Ciftci et al., 2024; Malireddi et al., 2019). Notably, emerging evidence reveals functional diversification beyond canonical non-coding roles: a subset of lncRNAs encodes regulatory peptides that orchestrate cellular functions through ribosome-independent mechanisms. This creates a molecular duality that, coupled with precise spatiotemporal expression patterns, positions these molecules as ideal candidates for biomarker development and therapeutic targeting (Bakhti and Latifi-Navid, 2022; Wu et al., 2020; Xing et al., 2021). Future research must address three critical imperatives to leverage this potential: systematically mapping lncRNA-peptide interactomes in neural death pathways using advanced crosslinking immunoprecipitation; resolving region-specific regulatory networks via integrated single-cell/spatial omics; and validating evolutionary conservation of functional motifs through cross-species models. Achieving this will enable CRISPR-engineered organoid platforms to accelerate lncRNA-targeted neurotherapeutic translation.

 Author contributions

ZX: Funding acquisition, Writing – original draft. CS: Writing – original draft. SH: Writing – review and editing, Conceptualization.

 Funding

The author(s) declare that financial support was received for the research and/or publication of this article. This work was financially supported by grants from the Chengdu Municipal Science and Technology Program (2022-YF05-01279-SN) and the Scientific Research Project of the Chengdu Health Commission (2022414).

We would like to thank Yi Qu for her helpful comments during manuscript preparation.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Generative AI statement

The authors declare that no Generative AI was used in the creation of this manuscript.

 Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

 References Ai Y. Meng Y. Yan B. Zhou Q. Wang X. (2024). The biochemical pathways of apoptotic, necroptotic, pyroptotic, and ferroptotic cell death. Mol. Cell 84 170–179. 10.1016/j.molcel.2023.11.040 38181758 Amgalan D. Chen Y. Kitsis R. N. (2017). death receptor signaling in the heart: Cell survival. apoptosis, and necroptosis. Circulation 136 743–746. 10.1161/CIRCULATIONAHA.117.029566 28827219 Bai H. Zhang Q. (2021). Activation of NLRP3 inflammasome and onset of Alzheimer’s disease. Front. Immunol. 12:701282. 10.3389/fimmu.2021.701282 34381452 Bakhti S. Z. Latifi-Navid S. (2022). Non-coding RNA-Encoded peptides/proteins in human cancer: The future for cancer therapy. Curr. Med. Chem. 29 3819–3835. 10.2174/0929867328666211111163701 34766886 Bernard A. Jin M. Xu Z. Klionsky D. J. (2015). A large-scale analysis of autophagy-related gene expression identifies new regulators of autophagy. Autophagy 11 2114–2122. 10.1080/15548627.2015.1099796 26649943 Bertheloot D. Latz E. Franklin B. S. (2021). Necroptosis, pyroptosis and apoptosis: An intricate game of cell death. Cell Mol. Immunol. 18 1106–1121. 10.1038/s41423-020-00630-3 33785842 Cao B. Wang T. Qu Q. Kang T. Yang Q. (2018). Long noncoding RNA SNHG1 promotes neuroinflammation in parkinson’s disease via regulating miR-7/NLRP3 pathway. Neuroscience 388 118–127. 10.1016/j.neuroscience.2018.07.019 30031125 Chen C. Huang Y. Xia P. Zhang F. Li L. Wang E. (2021). Long noncoding RNA Meg3 mediates ferroptosis induced by oxygen and glucose deprivation combined with hyperglycemia in rat brain microvascular endothelial cells, through modulating the p53/GPX4 axis. Eur. J. Histochem. 65:3224. 10.4081/ejh.2021.3224 34587716 Chen D. Xu Y. Gao X. Zhu X. Liu X. Yan D. (2023). A novel signature of cuproptosis-related lncRNAs predicts prognosis in glioma: Evidence from bioinformatic analysis and experiments. Front. Pharmacol. 14:1158723. 10.3389/fphar.2023.1158723 37101543 Chen S. Chen Y. Zhang Y. Kuang X. Liu Y. Guo M. (2020). Iron metabolism and ferroptosis in epilepsy. Front. Neurosci. 14:601193. 10.3389/fnins.2020.601193 33424539 Chen S. Wang M. Yang H. Mao L. He Q. Jin H. (2017). LncRNA TUG1 sponges microRNA-9 to promote neurons apoptosis by up-regulated Bcl2l11 under ischemia. Biochem. Biophys. Res. Commun. 485 167–173. 10.1016/j.bbrc.2017.02.043 28202414 Chen Y. Zhang L. Yu H. Song K. Shi J. Chen L. (2018). Necrostatin-1 improves long-term functional recovery through protecting oligodendrocyte precursor cells after transient focal cerebral ischemia in mice. Neuroscience 371 229–241. 10.1016/j.neuroscience.2017.12.007 29247776 Cho Y. S. Challa S. Moquin D. Genga R. Ray T. D. Guildford M. (2009). Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137 1112–1123. 10.1016/j.cell.2009.05.037 19524513 Christgen S. Kanneganti T. D. (2020). Inflammasomes and the fine line between defense and disease. Curr. Opin. Immunol. 62 39–44. 10.1016/j.coi.2019.11.007 31837596 Ciftci Y. C. Vatansever İE. Akgül B. (2024). Unraveling the intriguing interplay: Exploring the role of lncRNAs in caspase-independent cell death. Wiley Interdiscip. Rev. RNA. 15:e1862. 10.1002/wrna.1862 38837618 Deng J. Zhuang H. Shao S. Zeng X. Xue P. Bai T. (2024). Mitochondrial-Targeted copper delivery for cuproptosis-based synergistic cancer therapy. Adv. Healthc. Mater. 13:e2304522. 10.1002/adhm.202304522 38530073 Deng X. X. Li S. S. Sun F. Y. (2019). Necrostatin-1 prevents necroptosis in brains after ischemic stroke via inhibition of RIPK1-Mediated RIPK3/MLKL signaling. Aging Dis. 10 807–817. 10.14336/AD.2018.0728 31440386 Dikic I. Elazar Z. (2018). Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19 349–364. 10.1038/s41580-018-0003-4 29618831 Dixon S. J. Lemberg K. M. Lamprecht M. R. Skouta R. Zaitsev E. M. Gleason C. E. (2012). Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 149 1060–1072. 10.1016/j.cell.2012.03.042 22632970 Dixon S. J. Winter G. E. Musavi L. S. Lee, Snijder B. Rebsamen M. (2015). Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem. Biol. 10 1604–1609. 10.1021/acschembio.5b00245 25965523 Fan Y. Zhao X. Lu K. Cheng G. (2020). LncRNA BDNF-AS promotes autophagy and apoptosis in MPTP-induced Parkinson’s disease via ablating microRNA-125b-5p. Brain Res. Bull. 157 119–127. 10.1016/j.brainresbull.2020.02.003 32057951 Fernández A. Ordóñez R. Reiter R. J. González-Gallego J. Mauriz J. L. (2015). Melatonin and endoplasmic reticulum stress: Relation to autophagy and apoptosis. J. Pineal Res. 59 292–307. 10.1111/jpi.12264 26201382 Ferrer J. Dimitrova N. (2024). Transcription regulation by long non-coding RNAs: Mechanisms and disease relevance. Nat. Rev. Mol. Cell Biol. 25 396–415. 10.1038/s41580-023-00694-9 38242953 Gao L. Zhang A. (2023). Copper-instigated modulatory cell mortality mechanisms and progress in oncological treatment investigations. Front. Immunol. 14:1236063. 10.3389/fimmu.2023.1236063 37600774 Gao M. Yi J. Zhu J. Minikes A. M. Monian P. Thompson C. B. (2019). Role of mitochondria in ferroptosis. Mol. Cell 73 354–363.e3. 10.1016/j.molcel.2018.10.042 30581146 Ghafouri-Fard S. Hussen B. M. Jamali E. Branicki W. Taheri M. Akbari Dilmaghani N. (2022). Role of lncRNAs and circRNAs in epilepsy. Ageing Res. Rev. 82:101749. 10.1016/j.arr.2022.101749 36216292 Guo Y. Yang J. H. He Y. Zhou H. F. Wang Y. Ding Z. S. (2022). Protocatechuic aldehyde prevents ischemic injury by attenuating brain microvascular endothelial cell pyroptosis via lncRNA Xist. Phytomedicine 94:153849. 10.1016/j.phymed.2021.153849 34775360 He Y. Jing Y. Wei F. Tang Y. Yang L. Luo J. (2018). Long non-coding RNA PVT1 predicts poor prognosis and induces radioresistance by regulating DNA repair and cell apoptosis in nasopharyngeal carcinoma. Cell Death Dis. 9:235. 10.1038/s41419-018-0265-y 29445147 Herman A. B. Tsitsipatis D. Gorospe M. (2022). Integrated lncRNA function upon genomic and epigenomic regulation. Mol. Cell 82 2252–2266. 10.1016/j.molcel.2022.05.027 35714586 Hitomi J. Christofferson D. E. Ng A. Yao J. Degterev A. Xavier R. J. (2008). Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell 135 1311–1323. 10.1016/j.cell.2008.10.044 19109899 Huang S. Hou D. Zhang L. Pei C. Liang J. Li J. (2023). LncRNA MALAT1 promoted neuronal necroptosis in cerebral ischemia-reperfusion mice by stabilizing HSP90. Neurochem. Res. 48 3457–3471. 10.1007/s11064-023-03991-z 37470906 Huang Y. Xu W. Zhou R. (2021). NLRP3 inflammasome activation and cell death. Cell Mol. Immunol. 18 2114–2127. 10.1038/s41423-021-00740-6 34321623 Jawed R. Bhatti H. (2024). Cuproptosis in lung cancer: Therapeutic options and prognostic models. Apoptosis 29 1393–1398. 10.1007/s10495-024-01978-x 38735011 Jiang A. Luo P. Chen M. Fang Y. Liu B. Wu Z. (2022). A new thinking: Deciphering the aberrance and clinical implication of copper-death signatures in clear cell renal cell carcinoma. Cell Biosci. 12:209. 10.1186/s13578-022-00948-7 36581992 Jiang L. Kon N. Li T. Wang S. J. Su T. Hibshoosh H. (2015). Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520 57–62. 10.1038/nature14344 25799988 Jiang X. Stockwell B. R. Conrad M. (2021). Ferroptosis: Mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol. 22 266–282. 10.1038/s41580-020-00324-8 33495651 Jin J. Li R. Guo G. Chen Y. Li Z. A. Zheng J. (2023). Studies on the therapeutic and prognostic biomarkers of glioma using a novel cuproptosis-related IncRNA signature and validation in glioma. J. Environ. Pathol. Toxicol. Oncol. 42 53–70. 10.1615/JEnvironPatholToxicolOncol.2023047159 Jing H. Liu L. Jia Y. Yao H. Ma F. (2019). Overexpression of the long non-coding RNA oprm1 alleviates apoptosis from cerebral ischemia-reperfusion injury through the oprm1/miR-155/GATA3 axis. Artif. Cells Nanomed. Biotechnol. 47 2431–2439. 10.1080/21691401.2019.1626408 31187646 Kadakkuzha B. M. Liu X. A. McCrate J. Shankar G. Rizzo V. Afinogenova A. (2015). Transcriptome analyses of adult mouse brain reveal enrichment of lncRNAs in specific brain regions and neuronal populations. Front. Cell Neurosci. 9:63. 10.3389/fncel.2015.00063 25798087 Kaushik K. Leonard V. E. Kv S. Lalwani M. K. Jalali S. Patowary A. (2013). Dynamic expression of long non-coding RNAs (lncRNAs) in adult zebrafish. PLoS One 8:e83616. 10.1371/journal.pone.0083616 24391796 Khoshnam S. E. Moalemnia A. Anbiyaee O. Farzaneh M. Ghaderi S. (2024). LncRNA MALAT1 and ischemic stroke: Pathogenesis and opportunities. Mol. Neurobiol. 61 4369–4380. 10.1007/s12035-023-03853-3 38087169 Kitagawa M. Kitagawa K. Kotake Y. Niida H. Ohhata T. (2013). Cell cycle regulation by long non-coding RNAs. Cell Mol. Life Sci. 70 4785–4794. 10.1007/s00018-013-1423-0 23880895 Kleaveland B. Shi C. Y. Stefano J. Bartel D. P. (2018). A network of noncoding regulatory RNAs acts in the mammalian brain. Cell 174 350–362.e17. 10.1016/j.cell.2018.05.022 29887379 Kong R. Sun G. (2023). Targeting copper metabolism: A promising strategy for cancer treatment. Front. Pharmacol. 14:1203447. 10.3389/fphar.2023.1203447 37564178 Lane D. J. R. Metselaar B. Greenough M. Bush A. I. Ayton S. J. (2021). Ferroptosis and NRF2: An emerging battlefield in the neurodegeneration of Alzheimer’s disease. Essays Biochem. 65 925–940. 10.1042/EBC20210017 34623415 Lei Y. Klionsky D. J. (2021). The emerging roles of autophagy in human diseases. Biomedicines 9:1651. 10.3390/biomedicines9111651 34829881 Li K. Wang Z. (2023). lncRNA NEAT1: Key player in neurodegenerative diseases. Ageing Res. Rev. 86:101878. 10.1016/j.arr.2023.101878 36738893 Li M. M. Liu X. H. Zhao Y. C. Ma X. Y. Zhou Y. C. Zhao Y. X. (2020). Long noncoding RNA KCNQ1OT1 promotes apoptosis in neuroblastoma cells by regulating miR-296-5p/Bax axis. FEBS J. 287 561–577. 10.1111/febs.15047 31433907 Li R. Wang X. Zhu C. Wang K. (2022). lncRNA PVT1: A novel oncogene in multiple cancers. Cell Mol. Biol. Lett. 27:84. 10.1186/s11658-022-00385-x 36195846 Li Y. Guo S. Liu W. Jin T. Li X. He X. (2019). Silencing of SNHG12 enhanced the effectiveness of MSCs in alleviating ischemia/reperfusion injuries via the PI3K/AKT/mTOR signaling pathway. Front. Neurosci. 13:645. 10.3389/fnins.2019.00645 31293373 Li Z. Li J. Tang N. (2017). Long noncoding RNA Malat1 is a potent autophagy inducer protecting brain microvascular endothelial cells against oxygen-glucose deprivation/reoxygenation-induced injury by sponging miR-26b and upregulating ULK2 expression. Neuroscience 354 1–10. 10.1016/j.neuroscience.2017.04.017 28433650 Liang J. Wang Q. Li J. Q. Guo T. Yu D. (2020). Long non-coding RNA MEG3 promotes cerebral ischemia-reperfusion injury through increasing pyroptosis by targeting miR-485/AIM2 axis. Exp. Neurol. 325:113139. 10.1016/j.expneurol.2019.113139 31794744 Litwiniuk A. Juszczak G. R. Stankiewicz A. M. Urbańska K. (2023). The role of glial autophagy in Alzheimer’s disease. Mol. Psychiatry 28 4528–4539. 10.1038/s41380-023-02242-5 37679471 Liu L. Huang L. Chen W. Zhang G. Li Y. Wu Y. (2022). Comprehensive analysis of necroptosis-related long noncoding RNA immune infiltration and prediction of prognosis in patients with colon cancer. Front. Mol. Biosci. 9:811269. 10.3389/fmolb.2022.811269 35237659 Lu J. Xu F. Lu H. (2020). LncRNA PVT1 regulates ferroptosis through miR-214-mediated TFR1 and p53. Life Sci. 260:118305. 10.1016/j.lfs.2020.118305 32827544 Lu Y. Luo X. Wang Q. Chen J. Zhang X. Li Y. (2022). A novel necroptosis-related lncRNA signature predicts the prognosis of lung adenocarcinoma. Front. Genet. 13:862741. 10.3389/fgene.2022.862741 35368663 Lünemann J. D. Malhotra S. Shinohara M. L. Montalban X. Comabella M. (2021). Targeting inflammasomes to treat neurological diseases. Ann. Neurol. 90 177–188. 10.1002/ana.26158 34219266 Luo L. Li L. Liu L. Feng Z. Zeng Q. Shu X. (2022). A necroptosis-related lncRNA-Based signature to predict prognosis and probe molecular characteristics of stomach adenocarcinoma. Front. Genet. 13:833928. 10.3389/fgene.2022.833928 35330731 Mai C. Qiu L. Zeng Y. Jian H. G. (2019). LncRNA Lethe protects sepsis-induced brain injury via regulating autophagy of cortical neurons. Eur. Rev. Med. Pharmacol. Sci. 23 4858–4864. 10.26355/eurrev_201906_18073 31210319 Malireddi R. K. S. Kesavardhana S. Kanneganti T. D. (2019). ZBP1 and TAK1: Master regulators of NLRP3 inflammasome/pyroptosis, apoptosis, and necroptosis (PAN-optosis). Front. Cell Infect. Microbiol. 9:406. 10.3389/fcimb.2019.00406 31850239 Mao Z. Nie Y. Jia W. Wang Y. Li J. Zhang T. (2023). Revealing prognostic and immunotherapy-sensitive characteristics of a novel cuproptosis-related LncRNA model in hepatocellular carcinoma patients by genomic analysis. Cancers (Basel) 15:544. 10.3390/cancers15020544 36672493 Mi L. Min X. Chai Y. Zhang J. Chen X. (2022). NLRP1 inflammasomes: A potential target for the treatment of several types of brain injury. Front. Immunol. 13:863774. 10.3389/fimmu.2022.863774 35707533 Mizushima N. Levine B. Cuervo A. M. Klionsky D. J. (2008). Autophagy fights disease through cellular self-digestion. Nature 451 1069–1075. 10.1038/nature06639 18305538 Najafov A. Mookhtiar A. K. Luu H. S. Ordureau A. Pan H. Amin P. P. (2019). TAM kinases promote necroptosis by regulating oligomerization of MLKL. Mol. Cell 75 457–468.e4. 10.1016/j.molcel.2019.05.022 31230815 Nascimento-Ferreira I. Santos-Ferreira T. Sousa-Ferreira L. Auregan G. Onofre I. Alves S. (2011). Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado-Joseph disease. Brain 134(Pt 5), 1400–1415. 10.1093/brain/awr047 21478185 Nitsche A. Stadler P. F. (2017). Evolutionary clues in lncRNAs. Wiley Interdiscip. Rev. RNA. 8:e1376. 10.1002/wrna.1376 27436689 Nixon R. A. (2013). The role of autophagy in neurodegenerative disease. Nat. Med. 19 983–997. 10.1038/nm.3232 23921753 Paerewijck O. Lamkanfi M. (2022). The human inflammasomes. Mol. Aspects Med. 88:101100. 10.1016/j.mam.2022.101100 35696786 Pang J. Vince J. E. (2023). The role of caspase-8 in inflammatory signalling and pyroptotic cell death. Semin. Immunol. 70:101832. 10.1016/j.smim.2023.101832 37625331 Prasad Panda S. Kesharwani A. Prasanna Mallick S. Prasanth D. Kumar Pasala P. Bharadwaj Tatipamula V. (2023). Viral-induced neuronal necroptosis: Detrimental to brain function and regulation by necroptosis inhibitors. Biochem. Pharmacol. 213:115591. 10.1016/j.bcp.2023.115591 37196683 Qian C. Ye Y. Mao H. Yao L. Sun X. Wang B. (2019). Downregulated lncRNA-SNHG1 enhances autophagy and prevents cell death through the miR-221/222 /p27/mTOR pathway in Parkinson’s disease. Exp. Cell Res. 384:111614. 10.1016/j.yexcr.2019.111614 31499060 Richard R. Mousa S. (2022). Necroptosis in Alzheimer’s disease: Potential therapeutic target. Biomed. Pharmacother. 152:113203. 10.1016/j.biopha.2022.113203 35665670 Riley J. S. Bock F. J. (2022). Voices from beyond the grave: The impact of apoptosis on the microenvironment. Biochim. Biophys. Acta Mol. Cell Res. 1869:119341. 10.1016/j.bbamcr.2022.119341 35987283 Ruffo P. De Amicis F. Giardina E. Conforti F. L. (2023). Long-noncoding RNAs as epigenetic regulators in neurodegenerative diseases. Neural Regen. Res. 18 1243–1248. 10.4103/1673-5374.358615 36453400 Schwarzer R. Laurien L. Pasparakis M. (2020). New insights into the regulation of apoptosis, necroptosis, and pyroptosis by receptor interacting protein kinase 1 and caspase-8. Curr. Opin. Cell Biol. 63 186–193. 10.1016/j.ceb.2020.02.004 32163825 Shao R. N. Bai K. H. Huang Q. Q. Chen S. L. Huang X. Dai Y. J. (2023). A novel prognostic prediction model of cuprotosis-related genes signature in hepatocellular carcinoma. Front. Cell Dev. Biol. 11:1180625. 10.3389/fcell.2023.1180625 37608927 Shen H. Liu C. Zhang D. Yao X. Zhang K. Li H. (2017). Role for RIP1 in mediating necroptosis in experimental intracerebral hemorrhage model both in vivo and in vitro. Cell Death Dis. 8:e2641. 10.1038/cddis.2017.58 28252651 Siddiqui M. A. Mukherjee S. Manivannan P. Malathi K. (2015). RNase L cleavage products promote switch from autophagy to apoptosis by caspase-mediated cleavage of beclin-1. Int. J. Mol. Sci. 16 17611–17636. 10.3390/ijms160817611 26263979 Tran H. T. Kratina T. Coutansais A. Michalek D. Hogan B. M. Lawlor K. E. (2024). RIPK3 cleavage is dispensable for necroptosis inhibition but restricts NLRP3 inflammasome activation. Cell Death Differ. 31 662–671. 10.1038/s41418-024-01281-x 38514849 Tsvetkov P. Coy S. Petrova B. Dreishpoon M. Verma A. Abdusamad M. (2022). Copper induces cell death by targeting lipoylated TCA cycle proteins. Science 375 1254–1261. 10.1126/science.abf0529 35298263 Van Opdenbosch N. Lamkanfi M. (2019). Caspases in cell death, inflammation, and disease. Immunity 50 1352–1364. 10.1016/j.immuni.2019.05.020 31216460 Wan P. Su W. Zhang Y. Li Z. Deng C. Li J. (2020). LncRNA H19 initiates microglial pyroptosis and neuronal death in retinal ischemia/reperfusion injury. Cell Death Differ. 27 176–191. 10.1038/s41418-019-0351-4 31127201 Wang J. Cao B. Han D. Sun M. Feng J. (2017). Long non-coding RNA H19 induces cerebral ischemia reperfusion injury via activation of autophagy. Aging Dis. 8 71–84. 10.14336/AD.2016.0530 28203482 Wang L. Q. Zheng Y. Y. Zhou H. J. Zhang X. X. Wu P. Zhu S. M. (2021). LncRNA-Fendrr protects against the ubiquitination and degradation of NLRC4 protein through HERC2 to regulate the pyroptosis of microglia. Mol. Med. 27:39. 10.1186/s10020-021-00299-y 33858325 Wang Q. Bin C. Xue Q. Gao Q. Huang A. Wang K. (2021). GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis. Cell Death Dis. 12:426. 10.1038/s41419-021-03718-4 33931597 Wang L. Li Y. Wang Y. Li J. Sun Y. Chen J. (2022). Identification of cuproptosis-related lncRNAs for prognosis and immunotherapy in glioma. J. Cell Mol. Med. 26 5820–5831. 10.1111/jcmm.17603 36317420 Wang S. Han X. Mao Z. Xin Y. Maharjan S. Zhang B. (2019). MALAT1 lncRNA induces autophagy and protects brain microvascular endothelial cells against oxygen-glucose deprivation by binding to miR-200c-3p and upregulating SIRT1 expression. Neuroscience 397 116–126. 10.1016/j.neuroscience.2018.11.024 30496821 Wei X. B. Jiang W. Q. Zeng J. H. Huang L. Q. Ding H. G. Jing Y. W. (2022). Exosome-Derived lncRNA NEAT1 exacerbates sepsis-associated encephalopathy by promoting ferroptosis through regulating miR-9-5p/TFRC and GOT1 axis. Mol. Neurobiol. 59 1954–1969. 10.1007/s12035-022-02738-1 35038133 Wu J. Yu H. Huang H. Shu P. Peng X. (2021). Functions of noncoding RNAs in glial development. Dev. Neurobiol. 81 877–891. 10.1002/dneu.22848 34402590 Wu P. Mo Y. Peng M. Tang T. Zhong Y. Deng X. (2020). Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA. Mol. Cancer 19:22. 10.1186/s12943-020-1147-3 32019587 Wu Y. Y. Kuo H. C. (2020). Functional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases. J. Biomed. Sci. 27:49. 10.1186/s12929-020-00636-z 32264890 Wu Z. Wu P. Zuo X. Yu N. Qin Y. Xu Q. (2017). LncRNA-N1LR enhances neuroprotection against ischemic stroke probably by inhibiting p53 phosphorylation. Mol. Neurobiol. 54 7670–7685. 10.1007/s12035-016-0246-z 27844279 Xing J. Liu H. Jiang W. Wang L. (2021). LncRNA-Encoded peptide: Functions and predicting methods. Front. Oncol. 10:622294. 10.3389/fonc.2020.622294 33520729 Xu Q. Guohui M. Li D. Bai F. Fang J. Zhang G. (2021). lncRNA C2dat2 facilitates autophagy and apoptosis via the miR-30d-5p/DDIT4/mTOR axis in cerebral ischemia-reperfusion injury. Aging (Albany NY) 13 11315–11335. 10.18632/aging.202824 33833132 Xu S. Wang J. Jiang J. Song J. Zhu W. Zhang F. (2020). TLR4 promotes microglial pyroptosis via lncRNA-F630028O10Rik by activating PI3K/AKT pathway after spinal cord injury. Cell Death Dis. 11:693. 10.1038/s41419-020-02824-z 32826878 Xue Z. Zhang Z. Liu H. Li W. Guo X. Zhang Z. (2019). lincRNA-Cox2 regulates NLRP3 inflammasome and autophagy mediated neuroinflammation. Cell Death Differ. 26 130–145. 10.1038/s41418-018-0105-8 29666475 Yan H. Rao J. Yuan J. Gao L. Huang W. Zhao L. (2017). Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate ischemic neuronal death by targeting miR-21/PDCD4 signaling pathway. Cell Death Dis. 8:3211. 10.1038/s41419-017-0047-y 29238035 Yan W. T. Yang Y. D. Hu X. M. Ning W. Y. Liao L. S. Lu S. (2022). Do pyroptosis, apoptosis, and necroptosis (PANoptosis) exist in cerebral ischemia? evidence from cell and rodent studies. Neural Regen. Res. 17 1761–1768. 10.4103/1673-5374.331539 35017436 Yan W. Chen Z. Y. Chen J. Q. Chen H. M. (2018). LncRNA NEAT1 promotes autophagy in MPTP-induced Parkinson’s disease through stabilizing PINK1 protein. Biochem. Biophys. Res. Commun. 496 1019–1024. 10.1016/j.bbrc.2017.12.149 29287722 Yang R. Yang B. Liu W. Tan C. Chen H. Wang X. (2023). Emerging role of non-coding RNAs in neuroinflammation mediated by microglia and astrocytes. J. Neuroinflamm. 20:173. 10.1186/s12974-023-02856-0 37481642 Yang S. H. Lee D. K. Shin J. Lee S. Baek S. Kim J. (2017). Nec-1 alleviates cognitive impairment with reduction of Aβ and tau abnormalities in APP/PS1 mice. EMBO Mol. Med. 9 61–77. 10.15252/emmm.201606566 27861127 Yang W. S. Kim K. J. Gaschler M. M. Patel M. Shchepinov M. S. Stockwell B. R. (2016). Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc. Natl. Acad. Sci. U. S. A. 113 E4966–E4975. 10.1073/pnas.1603244113 27506793 Yang W. S. SriRamaratnam R. Welsch M. E. Shimada K. Skouta R. Viswanathan V. S. (2014). Regulation of ferroptotic cancer cell death by GPX4. Cell 156 317–331. 10.1016/j.cell.2013.12.010 24439385 Yao L. Peng P. Ding T. Yi J. Liang J. (2024). m6A-Induced lncRNA MEG3 promotes cerebral ischemia-reperfusion injury via modulating oxidative stress and mitochondrial dysfunction by hnRNPA1/Sirt2 axis. Mol. Neurobiol. 61 6893–6908. 10.1007/s12035-024-04005-x 38358439 Yao P. Li Y. L. Chen Y. Shen W. Wu K. Y. Xu W. H. (2020). Overexpression of long non-coding RNA Rian attenuates cell apoptosis from cerebral ischemia-reperfusion injury via Rian/miR-144-3p/GATA3 signaling. Gene 737:144411. 10.1016/j.gene.2020.144411 32006596 Ye Y. Feng Z. Tian S. Yang Y. Jia Y. Wang G. (2022). HBO alleviates neural stem cell pyroptosis via lncRNA-H19/miR-423-5p/NLRP3 axis and improves neurogenesis after oxygen glucose deprivation. Oxid. Med. Cell Longev. 2022:9030771. 10.1155/2022/9030771 35178162 Yuan J. Amin P. Ofengeim D. (2019). Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat. Rev. Neurosci. 20 19–33. 10.1038/s41583-018-0093-1 30467385 Zeng Y. Qian S. Cao Y. Xiao W. (2024). Unravelling the complex interplay of cuproptosis, lncRNAs, and immune infiltration in Alzheimer’s disease: A step towards novel therapeutic targets. Ann. Hum. Biol. 51:2342531. 10.1080/03014460.2024.2342531 38771661 Zhan Q. Jeon J. Li Y. Huang Y. Xiong J. Wang Q. (2022). CAMK2/CaMKII activates MLKL in short-term starvation to facilitate autophagic flux. Autophagy 18 726–744. 10.1080/15548627.2021.1954348 34282994 Zhang G. Guo J. Zeng J. Zhang X. Chen R. Wang G. (2022). LncRNA SNHG14 is beneficial to oxygen glucose deprivation/reoxygenation-induced neuro-2a cell injury via mir-98-5p sequestration-caused BCL2L13 upregulation. Metab. Brain Dis. 37 2005–2016. 10.1007/s11011-022-01009-1 35678981 Zhang Y. Zhang Y. (2020). lncRNA ZFAS1 improves neuronal injury and inhibits inflammation, oxidative stress, and apoptosis by sponging mir-582 and upregulating NOS3 expression in cerebral ischemia/reperfusion injury. Inflammation 43 1337–1350. 10.1007/s10753-020-01212-1 32180078 Zhang Y. Li M. Li X. Zhang H. Wang L. Wu X. (2020). Catalytically inactive RIP1 and RIP3 deficiency protect against acute ischemic stroke by inhibiting necroptosis and neuroinflammation. Cell Death Dis. 11:565. 10.1038/s41419-020-02770-w 32703968 Zhang Y. Yang G. Luo Y. (2019). Long non-coding RNA PVT1 promotes glioma cell proliferation and invasion by targeting miR-200a. Exp. Ther. Med. 17 1337–1345. 10.3892/etm.2018.7083 30680011 Zhao J. Gao W. Yang Z. Li H. Gao Z. (2019). Nitration of amyloid-β peptide (1-42) as a protective mechanism for the amyloid-β peptide (1-42) against copper ion toxicity. J. Inorg. Biochem. 190 15–23. 10.1016/j.jinorgbio.2018.10.005 30342351 Zheng J. Conrad M. (2020). The metabolic underpinnings of ferroptosis. Cell Metab. 32 920–937. 10.1016/j.cmet.2020.10.011 33217331 Zhong J. Jiang L. Huang Z. Zhang H. Cheng C. Liu H. (2017). The long non-coding RNA Neat1 is an important mediator of the therapeutic effect of bexarotene on traumatic brain injury in mice. Brain Behav. Immun. 65 183–194. 10.1016/j.bbi.2017.05.001 28483659 Zhou Y. Lu M. Du R. H. Qiao C. Jiang C. Y. Zhang K. Z. (2016). MicroRNA-7 targets Nod-like receptor protein 3 inflammasome to modulate neuroinflammation in the pathogenesis of Parkinson’s disease. Mol. Neurodegener. 11:28. 10.1186/s13024-016-0094-3 27084336 Zhu H. Wang L. Chen J. Shen H. Chen Z. (2022). Mechanisms underlying abnormal expression of lncRNA H19 in neonatal hypoxic-ischemic encephalopathy. Am. J. Perinatol. 39 844–852. 10.1055/s-0040-1718947 33111281 Zhu W. Chen Z. Fu M. Li Q. Chen X. Li X. (2024). Cuprotosis clusters predict prognosis and immunotherapy response in low-grade glioma. Apoptosis 29 169–190. 10.1007/s10495-023-01880-y 37713112