The inflammatory response serves as a fundamental mechanism in the development of SA-AKI, which is intricately linked to the activation of inflammatory signaling pathways and the secretion of pro-inflammatory cytokines. NF-κB is a principal regulator of the inflammatory response and is associated with various diseases. NF-κB is composed of the dimeric subunits p50 and p65, along with the inhibitory subunit IκB (inhibitor of κB). When IκB kinase catalyzes the degradation of the IκB protein, the activated NF-κB forms a dimer that translocates into the nucleus to regulate gene expression, thereby promoting inflammation. The rapid activation of NF-κB, following the degradation of IκB, facilitates its dimerization and subsequent translocation to the nucleus, where it binds to the promoters of several genes, regulating their expression and contributing to the production of inflammatory factors (Sun, 2017; Lawrence, 2009). Moreover, the activation of NF-κB signaling has been associated with various LncRNAs, and reducing NF-κB activity has been suggested to have a positive impact on septic acute kidney injuries. NEAT1 is a well-studied lncRNA in the context of SA-AKI. Several studies have demonstrated that NEAT1 is significantly upregulated in sepsis-induced AKI in both cellular and mouse models. Silencing NEAT1 enhances cell viability and attenuates inflammatory responses (Zhou et al., 2022). Mechanistically, NEAT1 acts as a sponge for miR-22-3p, thereby alleviating the inhibition of its downstream target, CXCL12, and activating the NF-κB pathway. This activation exacerbates the inflammatory response and cellular damage, ultimately promoting the progression of SA-AKI (Feng et al., 2020). Additionally, let-7b-5p has been identified as a target of NEAT1; in HK2 cells, NEAT1 regulates the expression of TRAF6 through the adsorption of let-7b-5p, which subsequently promotes LPS-induced HK2 cell injury and inflammatory responses (Gao et al., 2020). Yang et al. (Yang J. et al., 2021) reported that NEAT1 regulates TXNIP expression by functioning as a sponge for miR-93-5p, which promotes apoptosis, inflammation, and oxidative stress, contributing to the exacerbation of LPS-induced HK2 cell injury. Furthermore, NEAT1 silencing has been shown to ameliorate LPS-induced inflammation by modulating macrophage M2 polarization (Wang and Guo, 2020). Notably, NEAT1 not only activates NF-κB signaling but is also regulated by it. In SA-AKI, the TLR4/NF-κB pathway has been reported to facilitate the overexpression of NEAT1 and its translocation from the nucleus to the cytoplasm. This translocation allows NEAT1 to bind to the scaffold protein receptor for activated protein C kinase 1 (Rack1), activating NLRP3 inflammatory vesicles and promoting the release of inflammatory mediators and responses (Xue et al., 2024). This suggests that there may be a positive feedback amplification mechanism between NEAT1 and NF-κB, whereby the expression of NEAT1 is regulated by NF-κB, which subsequently promotes the activation of NF-κB signaling. The presence of this positive feedback mechanism implies that during the development of SA-AKI, once one component is activated, it amplifies the signals, promotes the activation of the entire signaling pathway, and rapidly induces an inflammatory response. CRNDE has been identified as an oncogene in various cancers and is highly expressed in tumor cells. In the context of SA-AKI, CRNDE was significantly upregulated, promoting the release of inflammatory factors such as TNF-α, IL-6, IL-8, and IL-1β, which exacerbated LPS-induced cellular inflammatory injury. Mechanistically, CRNDE contributes to the increase in cytokines and inflammatory responses by sponging miR-146a, thereby activating the TLR2/NF-κB pathway (Wu S. et al., 2020). Additionally, silencing CRNDE effectively suppressed the activation of TLR3 and p65 in mouse kidney tissues, suggesting that inhibition of CRNDE reduces sepsis-induced AKI by blocking the activation of the TLR3/NF-κB pathway (Sun BQ. et al., 2019). MALAT1 has previously been shown to promote inflammatory injury in the myocardium through the upregulation of TLR4 (Jia et al., 2019). Xu et al. (Xu et al., 2020) also reported that MALAT1 was elevated in both serum from sepsis patients and in an LPS-induced SA-AKI cell model, and its overexpression further aggravated cellular injury. Mechanistically, MALAT1 sponges miR-370-3p, attenuating the inhibition of the target gene HMGB1 by miR-370-3p, which increases the expression of inflammatory mediators such as TNF-α, IL-6, and IL-1β, thereby promoting cellular inflammatory injury. Importantly, paclitaxel prevented LPS-induced AKI by regulating the MALAT1/miR-370-3p/HMGB1 axis, indicating that paclitaxel may serve as a therapeutic agent to mitigate SA-AKI. Furthermore, resveratrol can improve inflammation and protect against SA-AKI by downregulating MALAT1. In resveratrol-treated sepsis model rats, the expression of MALAT1 was downregulated, the secretion of inflammatory factors in serum was reduced, and renal function was improved (Wang B. et al., 2021). LncRNA PVT1 has been implicated in various human diseases, including SA-AKI. Several studies have demonstrated that PVT1 expression is upregulated in the sera of SA-AKI patients, as well as in animal and cellular models of SA-AKI. Notably, the knockdown of PVT1 has been shown to alleviate sepsis-induced acute kidney injury. Furthermore, some studies indicate that PVT1 functions as a sponge for miR-17-5p, thereby activating the NF-κB pathway, which promotes inflammatory responses and apoptosis, leading to increased cellular damage upon LPS stimulation (Yuan et al., 2021). Additionally, Yang et al. (Yang et al., 2022) reported that PVT1 regulates the expression of OXSR1 by targeting miR-27a-3p, modulating the secretion of inflammatory cytokines, cell proliferation, and apoptosis, and promoting LPS-induced injury in HK-2 cells. Curcumin has been reported to exert a protective effect against SA-AKI, potentially through the inhibition of PVT1 and the JNK/NF-κB pathway. Huang et al. (Huang et al., 2020) found that curcumin treatment reduced serum creatinine (Scr) and blood urea nitrogen (BUN) levels, as well as decreased the expression of PVT1 and JNK/NF-κB pathway proteins in the renal tissues of mice with SA-AKI. In contrast, the overexpression of PVT1 diminished the therapeutic effects of curcumin. Furthermore, SNHG14 has been reported to have oncogenic functions in various malignant tumors (Dong H. et al., 2018). The role of SNHG14 in sepsis-induced AKI has been highlighted in several studies. Yang et al. (Yang N. et al., 2021) found that SNHG14 was highly expressed in the plasma of patients with sepsis combined with AKI. In vitro studies revealed that SNHG14 inhibited LPS-stimulated proliferation and autophagy of HK-2 cells while promoting apoptosis and the production of inflammatory cytokines. Mechanistically, SNHG14 acts as a ceRNA that negatively regulates the expression of miR-495-3p, thereby alleviating the inhibitory effect of miR-495-3p on its target gene, HIPK1. Moreover, the SNHG14/miR-495-3p/HIPK1 interaction network regulates the NF-κB pathway and promotes the production of inflammatory cytokines such as TNF-α, IL-6, and IL-2β. In addition, several other LncRNAs have been reported to promote inflammation and exacerbate sepsis-induced AKI. For instance, TCONS_00016233 functions as a ceRNA that inhibits the miR-22-3p-mediated downregulation of the apoptosis-inducing factor, mitochondria-associated 1 (AIFM1). This inhibition subsequently enhances the expression of inflammatory cytokines such as IL-1β and TNF-α (Zhang et al., 2020). Additionally, TapSAKI negatively regulates miR-22 expression, thereby upregulating PTEN and proteins associated with the TLR4/NF-κB signaling pathway, which in turn increases the levels of the apoptotic protein cleaved-caspase-3 and inflammatory factors (Shen et al., 2019). Furthermore, KCNQ1OT1 has been shown to be upregulated in LPS-stimulated HK2 cells; its overexpression leads to heightened apoptosis and inflammatory responses, worsening kidney injury. Mechanistically, KCNQ1OT1 has been identified as a miR-212-3p-regulated ceRNA for mitogen-activated protein kinase 1 (MAPK1), which activates the p38/NF-κB pathway (Wang H. et al., 2021).

In the study of SA-AKI, various protective lncRNAs have been identified, which can attenuate the inflammatory response and ameliorate sepsis-induced acute kidney injury by inhibiting inflammatory signaling pathways and the release of inflammatory factors. CASC2 has been linked to a range of human diseases, where it inhibits cell proliferation, invasion, and metastasis, while promoting apoptosis (Huang et al., 2019). Wang et al. (2020a) reported that the serum expression of CASC2 was significantly lower in sepsis patients compared to healthy subjects, and its levels were negatively correlated with the severity of AKI. Further studies demonstrated that CASC2 inhibited the secretion of inflammatory factors, apoptosis, and oxidative stress. Mechanistically, CASC2 directly binds to miR-155 to inhibit its expression. Additionally, CASC2 can attenuate the NF-κB signaling pathway in SA-AKI (Wang et al., 2020b). Lu et al. (2024) reported that NORAD was significantly downregulated in the renal tissues of SA-AKI, while overexpression of NORAD mitigated LPS-induced cellular damage. Bioinformatics analysis and luciferase assays indicated that NORAD downregulated the expression of miR-155-5p, which inhibits glucose metabolism by directly targeting the glucose-metabolizing enzyme pyruvate dehydrogenase kinase 1 (PDK1). Wu et al. (Wu et al., 2020a) investigated the role of HOXA-AS2 in SA-AKI, revealing that HOXA-AS2 expression was reduced in septic patients, animal models of septic kidney injury, and LPS-stimulated HK-2 cells. Overexpression of HOXA-AS2 alleviated sepsis-induced kidney injury. Mechanistically, HOXA-AS2 inhibited the Wnt/β-catenin and NF-κB pathways by targeting miR-106b-5p, thereby alleviating the inflammatory response and exhibiting a protective effect in SA-AKI. DANCR, a novel lncRNA, has been implicated in the pathophysiology of SA-AKI, as evidenced by the reduced serum levels of DANCR in patients with AKI and in LPS-treated HK-2 cells (Zhao et al., 2020). Furthermore, DANCR was found to enhance cell viability while inhibiting apoptosis and cytokine production in LPS-treated HK-2 cells. Mechanistically, DANCR interacts with miR-214, thereby inhibiting the expression of Krüppel-like factor 6 (KLF6), which is known to promote the expression of inflammatory factors in renal diseases (Rane et al., 2019). Li et al. (2021) reported that the expression levels of LINC00261 in the serum of sepsis patients were significantly lower than those in healthy controls, a finding corroborated by similar results in animal models. Further investigations revealed that the overexpression of LINC00261 increased cell viability and decreased inflammatory cytokine production in LPS-treated HK-2 cells. Mechanistically, LINC00261 functions as a sponge for miR-654-5p, which inhibits NF-κB activity by targeting suppressor of cytokine signaling 3 (SOCS3). In a study screening differentially expressed lncRNAs in LPS-exposed HK-2 cells, Lin et al. (2024) identified AP001007 as a potential regulator of SA-AKI, a conclusion supported by the observation of reduced AP001007 expression in the peripheral blood of sepsis patients. Functional analyses demonstrated that increased AP001007 expression mitigated LPS-induced injury in HK-2 cells, enhanced cell viability, protected mitochondrial function, promoted cell survival, and inhibited the secretion of pro-inflammatory cytokines. Similar protective effects were also observed in human kidney-like organs exposed to LPS.

In summary, LncRNA-mediated inflammatory responses significantly contribute to the development and progression of SA-AKI. Pro-inflammatory LncRNAs can activate relevant signaling pathways, such as NF-κB, which promotes the release of inflammatory factors and exacerbates the progression of SA-AKI. Conversely, protective LncRNAs can inhibit the inflammatory signaling pathways, thereby suppressing the progression of SA-AKI.

Apoptosis is the process of programmed cell death triggered by the activation of a series of apoptotic proteins regulated by apoptotic genes. Initially, SA-AKI was thought to result from ischaemia and necrosis of renal tubular cells due to sepsis; however, subsequent animal experiments and human data have demonstrated that most patients with SA-AKI do not exhibit reduced renal blood flow perfusion. Pathological examinations of SA-AKI patients revealed a significant increase in apoptosis of renal tubular epithelial cells, strongly suggesting that apoptosis plays a crucial role in the pathogenesis of SA-AKI (Lerolle et al., 2010; Aslan et al., 2018). Certain lncRNAs are implicated in the pathological processes of SA-AKI by mediating apoptosis. In a study examining the role of lncRNA HOTAIR in acute kidney injury in septic rats (Jiang et al., 2019), levels of TNF-α and IL-1β were elevated, and renal tissue cells exhibited signs of apoptosis compared to controls. Conversely, the introduction of lncRNA HOTAIR mimics significantly improved the renal histopathological morphology in septic rats, leading to a marked decrease in TNF-α and IL-1β levels, as well as reduced apoptosis in renal tissues. Mechanistically, lncRNA HOTAIR inhibited the expression of miR-34a, thereby alleviating the repression of miR-34a on its target gene Bcl-2, which in turn inhibited renal tissue apoptosis and mitigated AKI in septic rats. Additionally, lncRNA PMS2L2 has been identified as an inhibitor of LPS-induced inflammation (Yu et al., 2021). Zhang et al. (2023) reported that plasma levels of PMS2L2 were significantly downregulated in SA-AKI patients. Moreover, miR-21, known to inhibit sepsis-induced renal injury, was also significantly downregulated in the SA-AKI group (Zhang et al., 2021a; Pan et al., 2019). In the plasma of SA-AKI patients, the expressions of PMS2L2 and miR-21 were positively correlated. Mechanistically, PMS2L2 can upregulate miR-21 by reducing the methylation of the miR-21 gene, thereby protecting podocytes from LPS-induced apoptosis (Zhang et al., 2023) Ding et al. (Ding et al., 2021) identified differentially expressed lncRNAs through RNA sequencing in a rat model of SA-AKI. Notably, the expression level of lncRNA NONRATG019935.2 (9,952) demonstrated the most significant reduction in both septic AKI rats and LPS-treated NRK-52E cells. Overexpression of 9,935 inhibited c-caspase three expression in LPS-treated NRK-52E cells and delayed the progression of septic AKI. Mechanistically, 9,935 reduced HuR-mediated p53 mRNA stability by limiting the binding of human antigen R (HuR) to the 3′untranslated region (UTR) of p53 mRNA. This indicates that 9,935 plays a role in septic AKI by inhibiting p53-mediated apoptosis of renal tubular epithelial cells, and that this critical function of 9,935 is contingent upon its disruptive effect on HuR-mediated p53 mRNA stability.

Oxidative stress refers to a state of imbalance between oxidative and antioxidant effects within the body, resulting in the accumulation of reactive oxygen species (ROS). The excessive release of ROS into the cytoplasm leads to the oxidative modification of proteins and lipids, which ultimately causes oxidative damage and severely impacts cellular function. Numerous studies have established that oxidative stress occurs during sepsis-associated acute kidney injury (SA-AKI), and heightened oxidative stress exacerbates SA-AKI. LncRNA GAS6-AS2 has been reported to be upregulated in LPS-treated HK2 cells and in a CLP-induced rat model. The knockdown of GAS6-AS2 resulted in decreased levels of ROS and malondialdehyde (MDA), alongside increased superoxide dismutase (SOD) levels, indicating a reduction in oxidative stress. Furthermore, serum creatinine (sCr) and blood urea nitrogen (BUN) levels were also reduced, leading to the amelioration of renal injury. Mechanistically, GAS6-AS2 acts as a sponge for miR-136-5p, thereby mitigating the inhibitory effect of miR-136-5p on the downstream target gene OXSR1 (Mercier-Zuber and O'Shaughnessy, 2011). OXSR1 is a serine/threonine kinase that regulates downstream kinases in response to environmental stress and is responsible for the co-transport of ions in the kidneys. OXSR1 plays a critical role in influencing the apoptotic process and is a key regulator of both oxidative stress and inflammatory pathways (Chen et al., 2004; Cusick et al., 2006; Qin et al., 2019). Additionally, SNHG14 may contribute to LPS-induced oxidative stress in HK-2 cells, with SNHG14 overexpression further enhancing SA-AKI via oxidative stress (Shi et al., 2021).

In contrast, the overexpression of certain lncRNAs has been shown to inhibit oxidative stress and ameliorate renal injury. CASC9 has been reported to play a protective role in sepsis-induced organ damage (Wang et al., 2020c). Fan et al. (2021) demonstrated that CASC9 was significantly downregulated in a LPS-induced AKI model. Conversely, the overexpression of CASC9 mitigated cellular inflammation and apoptosis while enhancing cellular antioxidant capacity. Mechanistically, miR-424-5p has been identified as a downstream target of CASC9, and the interaction between CASC9 and miR-424-5p promotes the expression of thioredoxin-interacting protein (TXNIP), which has previously been implicated in the regulation of renal oxidative stress in AKI (Wen et al., 2018; Ji et al., 2019). Furthermore, the overexpression of lncRNA TCONS_00016406 alleviates SA-AKI by suppressing oxidative stress. Mechanistically, lncRNA TCONS_00016406 acts as a sponge for miRNA-687, which in turn alleviates SA-AKI by activating the miR-687/PTEN signaling pathway (Liu et al., 2020).

In summary, oxidative stress induces oxidative damage in cells and facilitates the progression of SA-AKI. Modulating oxidative stress by regulating the expression of related LncRNAs may ameliorate sepsis-induced renal injury, suggesting that targeting oxidative stress-related LncRNAs represents a promising strategy for the treatment of SA-AKI.

Scorch death represents a distinct form of regulated cell death, characterized by cell swelling and membrane rupture, which leads to the release of intracellular contents and the activation of potent inflammatory responses (Ding et al., 2016). Cellular pyroptosis is primarily mediated by the activation of inflammatory vesicles. In the context of sepsis and acute kidney injury, the most extensively studied inflammatory vesicle is NLRP3, which is activated in response to stimulation by PAMPs and DAMPs. These stimuli subsequently recruit and activate cysteine aspartic proteases, predominantly caspase-1. The activation of caspase-1 triggers the cleavage of Gasdermin D (GSDMD), a key protein responsible for pore formation in the plasma membrane. The N-terminal fragment of GSDMD oligomerizes to create a pore in the cell membrane, leading to cell lysis and the release of cellular contents. The unique structure of the kidney, particularly the high metabolic demands of renal tubular epithelial cells, renders them highly susceptible to pyroptotic injury (Li et al., 2022). Pyroptosis results in tubular necrosis, impaired filtration, and ultimately renal failure (Wu et al., 2025). In recent years, there has been increasing evidence that cellular juxtaposition plays a key role in the pathophysiology of SA-AKI (Z et al., 2024; Sun et al., 2024; Liu et al., 2025). Cellular juxtaposition in SA-AKI is associated with LncRNAs. Deng et al. (Deng et al., 2021a) reported that PVT1 expression was upregulated and cellular juxtaposition was increased in both animal and cellular models of SA-AKI. Notably, PVT1 knockdown significantly inhibited cellular pyroptosis. Mechanistically, PVT1 functions as a sponge for miR-20a-5p, which directly targets NLRP3, suggesting that PVT1 promotes cellular juxtaposition through the miR-20a-5p/NLRP3 signaling pathway, thereby exacerbating sepsis-induced AKI. Additionally, LncRNA MEG3-mediated juxtaposition of renal tubular epithelium plays a crucial role in the pathogenesis of SA-AKI. Silencing of MEG3 downregulated GSDMD expression and reduced focal cell death. Furthermore, MEG3 regulates the expression of GSDMD by acting as a competing endogenous RNA (ceRNA) for miR-18a-3p, which promotes focal death of tubular epithelial cells (TECs) (Deng et al., 2021b). These studies suggest that certain LncRNAs can promote cellular pyroptosis in SA-AKI and facilitate its progression. Therefore, targeted inhibition of the pyroptosis pathway and related LncRNAs may represent a potential strategy for the treatment of SA-AKI.

In contrast, certain LncRNAs have been shown to inhibit cellular pyroptosis, thereby improving the prognosis of SA-AKI. Hua et al. (Ling et al., 2021) reported that LncRNA GAS5 was downregulated in both in vitro and in vivo models of sepsis-induced kidney injury. Mechanistically, GAS5 negatively regulates miR-579-3p, which diminishes the inhibitory effect of miR-579-3p on its target gene SIRT1. This interaction further activates the SIRT1/PGC-1α/Nrf2 signaling pathway, leading to the inhibition of cellular focal death and the mitigation of sepsis-induced kidney injury.

Autophagy is a form of programmed cell death characterized by a self-digestive process in which cells utilize lysosomes to degrade their own damaged, denatured, or senescent macromolecules and organelles, influenced by external environmental factors. Autophagy can provide energy and promote cell survival through a circulatory mechanism under metabolic stress; however, excessive autophagy can lead to autophagic cell death (Chen et al., 2024). Autophagy plays a crucial role in the pathogenesis of SA-AKI, with LncRNAs reported to influence the progression of SA-AKI by regulating autophagy. The expression of LncRNA MIAT has been shown to be upregulated in patients with SA-AKI and in LPS-stimulated HK-2 cells. Downregulation of MIAT attenuated autophagy and enhanced cell viability. Mechanistically, MIAT activates BECN1-mediated cellular autophagy by interacting with PTBP1, and the elimination of BECN1 significantly reverses the effect of MIAT silencing on cell viability (Xu and Zhou, 2023). Additionally, SNHG14-mediated autophagy is associated with SA-AKI; specifically, SNHG14 sponges miR-373-3p and reduces the inhibition of its target gene, ATG7, by miR-373-3p, thereby promoting autophagy and the progression of SA-AKI (Yang et al., 2024). Interestingly, the expression of SNHG14 is regulated by m6A modification, with FTO removing the m6A modification of SNHG14, which decreases its stability and hinders its expression (Yang et al., 2024). In summary, LncRNA-mediated autophagy promotes the progression of SA-AKI, and the inhibition of autophagy and associated LncRNAs presents a promising strategy for the treatment of SA-AKI. However, due to the dual nature of autophagy, its exact role in SA-AKI remains uncertain and requires further investigation.

The rate of cell proliferation is closely correlated with the repair of tissue cells; when normal cell proliferation is inhibited, it tends to exacerbate disease progression. In the context of sepsis, renal cell proliferation is suppressed, thereby worsening AKI. Several lncRNAs regulate cell proliferation, thereby influencing the progression of SA-AKI. For instance, SNHG14 has been shown to inhibit LPS-stimulated proliferation of HK-2 cells (Yang et al., 2021). Additionally, MALAT1 is found to be elevated in both serum and LPS-injured cells from septic patients, where it also inhibits cell proliferation (Xu et al., 2020). Furthermore, the silencing of NEAT1 mitigates the LPS-induced inhibition of cell proliferation (Gao et al., 2020). These findings suggest that cell proliferation is inhibited in the context of sepsis, and that modulation of the relevant lncRNAs can alleviate this inhibition, thereby potentially mitigating the progression of SA-AKI.

Ferroptosis is a novel form of cell death characterized by lipid peroxidation, glutathione depletion (GSH), and the inactivation of glutathione peroxidase 4 (GPX4). Recent studies have emphasized the significant correlation between ferroptosis and SA-AKI. Furthermore, lncRNAs have been shown to regulate iron death, thereby influencing the progression of SA-AKI. One study demonstrated that MALAT1 promotes iron death, thereby accelerating the progression of SA-AKI. Conversely, silencing MALAT1 inhibits ferroptosis and mitigates renal injury. Mechanistically, MALAT1 enhances the stability of ACSF2 mRNA by interacting with FUS. Through its interaction with FUS, MALAT1 contributes to ferroptosis and exacerbates SA-AKI by stabilizing ACSF2 mRNA (Duan et al., 2024).