Hepatocytes, the principal parenchymal cells in the liver, undertake a plethora of functions under physiological conditions, including metabolism, bile secretion, detoxification, and the synthesis of proteins and lipids (Neshat et al., 2021). Hepatocyte injury and death, caused by various etiological factors, are critical initial events in all liver diseases. Necrotic hepatocytes release damage-associated molecular pattern (DAMP) molecules and inflammatory mediators, which signal the immune system and are pivotal in the progression of fibrosis and inflammation (Gong et al., 2022). Inflammatory mediators incite the activation and proliferation of HSCs. Upon activation, HSCs transdifferentiate into myofibroblasts, which proliferate and secrete extracellular matrix (ECM) proteins, thereby perpetuating the progression of fibrosis (Liedtke et al., 2021). DAMPs released from the mitochondria of injured hepatocytes can directly activate HSCs, thereby accelerating liver fibrosis (An et al., 2020). Studies have shown that silencing lncRNA AK139328 enhances the levels of pAkt and p-eNOS, while reducing hepatocyte death in liver ischemia/reperfusion, thereby demonstrating a protective effect against ischemia/reperfusion injury (IRI) in the liver (Chen et al., 2013). Therefore, therapies aimed at protecting hepatocytes from injury are considered key strategies for treating liver fibrosis.

Hepatic stellate cells (HSCs), residing within the space of Disse between hepatocytes and liver sinusoidal endothelial cells (LSECs), undergo aberrant activation that constitutes a principal mechanism in the pathogenesis of liver fibrosis (Liu P. et al., 2022). Under normal physiological conditions, HSCs remain in a quiescent state. However, during liver injury, damaged hepatocytes release components such as DAMPs, which stimulate the transition of quiescent HSCs to activated HSCs. These activated HSCs proliferate and transdifferentiate into proliferative and contractile myofibroblasts. Myofibroblasts secrete type I collagen and α-smooth muscle actin (α-SMA), thereby facilitating the repair of damaged hepatic tissue. The regression of liver fibrosis is associated with the diminution or depletion of HSCs, indicating that deactivating or diminishing HSCs may represent a viable antifibrotic strategy, irrespective of the etiology of liver injury (Tsuchida and Friedman, 2017). Moreover, transforming growth factor-β (TGF-β) is pivotal in the activation of HSCs and is regarded as one of the key profibrogenic cytokines in the liver. Under normal conditions, hepatocytes produce low levels of TGF-β. However, following acute and chronic liver injury, TGF-β secretion significantly increases, activating HSCs to secrete ECM proteins (Dewidar et al., 2019). Chronic injury leads to sustained HSC activation, causing an imbalance between ECM synthesis and degradation, resulting in the excessive accumulation of ECM and the development of liver fibrosis (Roehlen et al., 2020). Reports suggest that TET3, a member of the TET dioxygenase family, promotes TGF-β expression in hepatocytes. Conversely, miRNA let-7 exhibits antifibrotic activity by suppressing TGF-β1 production via TET3 downregulation in hepatocytes (Song et al., 2023).

Liver sinusoidal endothelial cells (LSECs) serve as a critical barrier between other hepatic cell types and blood, facilitating the exchange of substances between the circulatory system and the space of Disse. In normal hepatic tissue, LSECs display anti-inflammatory, antifibrotic, and immunomodulatory functions, playing a pivotal role in maintaining hepatic homeostasis (Gracia-Sancho et al., 2021). Under normal physiological conditions, LSECs have the capacity to maintain HSC quiescence and support hepatocyte regeneration. However, when LSECs are damaged, they lose this capability, leading to HSC activation, which is critical for fibrosis progression (Koch et al., 2021).During liver injury, LSECs undergo capillarization, leading to diminished levels of vasodilators (e.g., cyclooxygenase-1, nitric oxide) and elevated levels of vasoconstrictors (e.g., endothelin-1, thromboxane A2), severely impairing liver function, activating HSCs, and promoting inflammation and fibrosis (Cheng QN. et al., 2021). Wang et al. identified elevated levels of miR-322/424 in patients with liver cirrhosis. These microRNAs promote fibrosis by targeting Cullin2, thereby enhancing HIF-1α activity to drive angiogenesis (Wang et al., 2021). It has been reported that overexpression of lncRNA Airn sustains LSEC differentiation via the KLF2-eNOS-sGC pathway, thereby preventing capillarization and indirectly suppressing HSCs activation. Furthermore, it boosts the paracrine secretion of HGF by LSECs, facilitating hepatocyte proliferation and mitigating liver fibrosis (Chen et al., 2022). Given the distinctive functions of LSECs, selectively targeting them for liver fibrosis treatment emerges as a promising novel therapeutic strategy.

The liver functions as an immune organ, hosting a diverse array of immune cells from both innate and adaptive immune systems, including neutrophils, lymphocytes, natural killer (NK) cells, and macrophages, each endowed with immunoregulatory capabilities (Xu et al., 2012). Among these, hepatic macrophages are pivotal in initiating inflammatory responses during liver injury, as well as in the development and resolution of liver fibrosis, making them viable targets for antifibrotic therapy (Zhao et al., 2022). Hepatic macrophages are non-parenchymal cells, accounting for 90% of the body’s total macrophages, predominantly composed of resident Kupffer cells (KCs) and macrophages derived from bone marrow monocytes (Cheng D. et al., 2021). Following liver injury or inflammatory stimuli, macrophages undergo polarization, categorized into pro-inflammatory (M1) and anti-inflammatory (M2) macrophages, based on their cytokine profiles (Papadakos et al., 2023). Hepatocytes exposed to intermittent hypoxia release exosomes enriched with miR-421, which suppress the SIRT3/AMPK pathway and subsequently promoting macrophage polarization toward the M1 phenotype (Yang L. et al., 2024). M1 macrophages secrete inflammatory cytokines, including TNF-α and IL-1, which induce the transformation of HSCs into myofibroblasts, thereby contributing to the progression of liver fibrosis. Additionally, inhibiting the Notch signaling pathway to reduce TNF-α secretion by M1 macrophages can alleviate liver fibrosis (Sheng et al., 2020). In a NASH mouse model, treatment with the miR-690 mimic inhibited the function of HSCs and M1 expression, while restoring the number and function of M2 macrophages, thereby attenuating fibrosis progression (Gao et al., 2022). Conversely, M2 macrophages express MMPs, such as MMP13, which degrade ECM and promote the resolution of liver fibrosis (Luo et al., 2019). Hence, liver macrophages exhibit a dual role in liver fibrosis, both promoting its progression and facilitating its resolution.

Iron is a vital trace element integral to human physiology (Ni et al., 2022), playing a pivotal role in fundamental biological processes, encompassing DNA synthesis and repair, mitochondrial respiration, and cellular signaling (Galy et al., 2024). In the body, iron primarily exists in two forms: ferrous ions (Fe²⁺) and ferric ions (Fe³⁺), which play a critical role in cellular functions via redox reactions (Estêvão et al., 2023). Iron metabolism primarily involves the absorption, storage, and utilization of iron (Correnti et al., 2022). In the intestine, dietary iron is reduced to Fe2+ by duodenal cytochrome B (DCYTB) and transported into the cytoplasm of enterocytes through divalent metal transporter 1 (DMT1) (Wang and Babitt, 2019). Within the cytoplasm, ferrous iron can be stored in ferritin or bind to ferroportin (FPN) to cross the basolateral membrane of enterocytes and enter the bloodstream (Pasquadibisceglie et al., 2023). Fe²⁺ is oxidized to Fe³⁺ by ceruloplasmin or hephaestin (HEPH), after which it binds to transferrin (TF), the plasma iron carrier.TF transports Fe³⁺ by engaging with transferrin receptor 1 (TFR1) on the cell membrane, forming a TF-Fe³⁺-TFR1 complex that is internalized via endocytosis, thereby delivering Fe³⁺ into peripheral tissue cells (Bayır et al., 2023). Intracellularly, Fe³⁺ is reduced to Fe²⁺ by the six-transmembrane epithelial antigen of the prostate 3 (STEAP3) ferrireductase. At this juncture, a minor fraction of Fe²⁺ constitutes the labile iron pool (LIP), whereas the majority is sequestered in an inactive form within cytoplasmic ferritin (FT) (Kouroumalis et al., 2023). Nevertheless, the bulk of circulating iron originates not from dietary absorption but from the recycling processes occurring within the body. This recycling predominantly transpires in the spleen and liver, where macrophages phagocytose and degrade iron-rich senescent erythrocytes (Sun et al., 2024) (Figure 3).

The liver functions as a pivotal organ for iron regulation. Hepatocytes produce substantial amounts of ferritin, facilitating excess iron storage and establishing the liver as the body’s primary iron reservoir (Sudarev et al., 2023). Additionally, hepatocytes synthesize and secrete hepcidin, a pivotal hormone in iron metabolism regulation that modulates transferrin activity (Baringer et al., 2023). Elevated hepcidin levels inhibit FPN activity, resulting in iron retention within cells and hindering its mobilization into the bloodstream for utilization by other tissues and organs (Nemeth and Ganz, 2023). In diverse hepatic pathologies, the levels and functionalities of associated proteins, including ferritin, transferrin, and hepcidin, are dysregulated, culminating in intracellular iron accumulation (Hsu et al., 2022).An elevation in the labile iron pool (LIP) is a significant source of intracellular oxidative stress (Wang et al., 2022). Ferrous iron within the LIP participates in the Fenton reaction, catalyzing the generation of hydroxyl radicals. It also partakes in lipid peroxidation reactions, producing lipid radicals such as LOO• and LO•, which attack macromolecules including lipids, proteins, and carbohydrates, leading to oxidative damage and eventual cell death (Gensluckner et al., 2024). Research have shown that miR-485-3p overexpression in HepG2 cell lines suppresses FPN expression and elevates intracellular ferritin levels, leading to the accumulation of intracellular iron (Sangokoya et al., 2013). Zhou et al. identified a significant positive correlation between peripheral blood levels of lncRNA NEAT1 and serum hepcidin in patients with NAFLD. They proposed that lncRNA NEAT1 may regulate hepcidin expression, promoting iron accumulation in hepatocytes and exacerbating cellular injury and death (Zhou and Qiu, 2022).

Lipids are crucial biological macromolecules that play essential roles in cellular life processes as components of cell membranes, organelle membranes (such as mitochondria and the endoplasmic reticulum), and signal transduction pathways (Gerhardtova et al., 2024). Phospholipids are fundamental structures in cell membranes, maintaining cell morphology and coordinating cellular functions. Additionally, phospholipids are highly susceptible to oxidation (Ferreira and Domingues, 2024). The sn-2 position of phospholipids is conjugated with acyl residues, frequently comprising polyunsaturated fatty acids (PUFAs). Due to their multiple double allylic hydrogen atoms, PUFAs exhibit heightened susceptibility to reactive oxygen species (ROS), culminating in the generation of phospholipid hydroperoxides (PLOOH) and free cholesterol. These molecules serve as substrates for lipid peroxidation, a pivotal process in ferroptosis, thereby compromising membrane structure and function (Wu et al., 2021; Zheng and Conrad, 2020).PUFA synthesis is orchestrated by an array of enzymes, notably acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), which mediate the incorporation of PUFAs into phosphatidylethanolamine within membrane phospholipids. ACSL4 and LPCAT3 are critical determinants of ferroptosis susceptibility and play a significant role in promoting ferroptosis (Liu J. et al., 2022). In a mouse model of acute myocardial infarction (AMI), myocardial ischemia leads to the accumulation of iron, ROS, and lipid peroxides, supporting the role of ischemia in inducing ferroptosis. Furthermore, miR-450b-5p expression was suppressed in ischemic myocardium. Overexpression of miR-450b-5p downregulated ACSL4 expression and attenuated ferroptosis, whereas miR-450b-5p inhibition produced the opposite effect (Yu et al., 2023). Zhang et al. identified in an acute kidney injury model that miR-124-3p.1 regulates LPCAT3 expression and modulates lipid metabolism, thereby exacerbating ferroptosis and aggravating kidney injury (Zhang H. et al., 2022). Lipid peroxidation can be initiated via non-enzymatic or enzymatic mechanisms. Fe²⁺ participate in non-enzymatic Fenton reactions, producing hydroperoxyl radicals (ROO) and hydroxyl radicals (HO). These radicals catalyze the oxidation of PUFAs, initiating lipid peroxidation, thereby intensifying oxidative stress and promoting cell death (Li X. et al., 2023). Lipid peroxidation can also be mediated by lipoxygenases (ALOXs). LOXs, which are non-heme iron-containing enzymes, can directly introduce oxygen into membrane PUFAs and PUFA-containing lipids, triggering peroxidation and ferroptosis (Maheshwari, 2023). Wu et al. identified circPtpn14 as a molecular sponge for miR-351-5p, modulating its expression. In a traumatic brain injury (TBI) model, circPtpn14 was significantly upregulated, resulting in the downregulation of miR-351-5p. Importantly, miR-351-5p suppressed 5-LOX expression. These results indicate that the circPtpn14/miR-351-5p/5-LOX axis enhances 5-LOX expression, facilitating ferroptosis (Wu C. et al., 2022).

In the human physiological system, several pathways protect against oxidative damage associated with ferroptosis. Ferroptosis can be induced through exogenous and endogenous pathways. The exogenous pathway involves inhibiting cell membrane transport proteins such as cystine/glutamate antiporter (also known as System Xc-, a crucial intracellular antioxidant element) or activating transferrin and lactotransferrin, which induce ferroptosis (Chen et al., 2021). The endogenous pathway involves blocking GPX4, the only intracellular glutathione peroxidase used for lipid peroxidation reduction (Liu et al., 2023). Amino acid metabolism, particularly that of cystine and glutathione, is key to preventing excessive ROS and maintaining normal cellular antioxidant status, and abnormalities in this metabolism are closely related to ferroptosis (Xu et al., 2024).

miRNA, a class of ncRNAs comprising 18–25 nucleotides, regulate protein translation by binding to the 3′untranslated regions (3′UTRs) of mRNAs, consequently inhibiting or inducing ferroptosis (Tabnak et al., 2021). In recent years, numerous studies have reported that miRNAs can mediate ferroptosis-related genes to regulate ferroptosis, thereby promoting or reversing liver fibrosis. miRNAs mediate ferroptosis to promote liver fibrosis. For example, in both in vivo and in vitro models of alcoholic liver disease (ALD), the overexpression of miR-192-5p markedly reduced the expression of fibronectin type III domain-containing protein 3B (FNDC3B) in hepatocytes. The depletion of FNDC3B markedly exacerbated ethanol-induced lipid peroxidation and iron overload, modulating ferroptosis to further exacerbate liver injury. Administering the ferroptosis inhibitor ferrostatin-1 (Fer-1) diminished FNDC3B inhibition-induced lipid peroxidation and ameliorated alcohol-induced liver injury (You et al., 2022). Luo et al. established an ALD model and found that miR-214 selectively binds to AGO2 protein in the nucleus, activating ferroptosis-driving genes (ACSL4, PRKAA2, and SLC38A1) to enhance ferroptosis in hepatocytes and exacerbate alcoholic liver injury (Luo J. et al., 2023). ALI has been shown to trigger ER stress-induced overexpression of Gα12, elevating miR-125a levels, suppressing NEMO expression, and downregulating GPX4, thereby intensifying hepatocellular ferroptosis (Tak et al., 2024). It has been reported that miR-15a is a downstream regulator of the Gα12 pathway in normal hepatocytes, directly interacting with the 3′-UTR of ALOX12 mRNA, thereby suppressing ALOX12 expression. In mice exposed to excessive acetaminophen (APAP) or in patients with acute liver injury or fibrosis, endoplasmic reticulum (ER) stress induces Gα12 overexpression, resulting in the downregulation of miR-15a levels. This leads to enhanced ALOX12 expression, which, through the accumulation of lipid hydroperoxides, depletes GSH and inhibits GPX4, thereby promoting ferroptosis in hepatocytes and exacerbating liver damage and fibrosis progression (Tak et al., 2022). Increased miR-222 expression in the serum of HCV-infected patients is particularly significant in both early and late stages of liver fibrosis, serving as a biomarker for detecting liver fibrosis (Abdel-Al et al., 2018). Zhang et al. found that TFRC is a downstream target of miR-222. Exosomal miR-222 from HBV-infected hepatocytes induces ferroptosis in LX-2 cells by inhibiting TFRC, ultimately aggravating liver fibrosis (Zhang Q. et al., 2023).

On the other hand, miRNAs can mediate ferroptosis to alleviate liver fibrosis. Hu et al. discovered that miR-142-3p expression is significantly enhanced in the peripheral blood of HBV-positive HCC patients, which can induce ferroptosis in M1 macrophages (Hu et al., 2022). Suppressing M1 macrophages decreases TNF-α levels, thereby mitigating liver fibrosis (Sheng et al., 2020). Cao et al. identified SLC7A11 as a downstream target of miR-26a through TargetScan and miRDB. In both in vivo and in vitro studies, mesenchymal stem cell-derived exosomal miR-26a was shown to inhibit HSCs activation by downregulating SLC7A11 expression, thereby promoting ferroptosis in HSCs and mitigating liver fibrosis (Cao et al., 2024). G-Rg3 induces ferroptosis in HSCs and mitigates liver fibrosis by reducing ACSL4 methylation via miR-6945-3p-mediated inhibition of DNMT3B (106). Steap3 is a reductase that converts ferric iron to ferrous iron, regulating intracellular iron homeostasis (Liu J. et al., 2021). A study found a binding site for miR-124-3p in Steap3. Using a rat liver transplantation model and hepatocyte hypoxia and reoxygenation (H/R) model, they injected heme oxygenase-1 (HO-1) modified bone marrow mesenchymal stem cell (BMMSC)-derived exosomes (HM-exos). These HM-exos, rich in miR-124-3p, inhibited STEAP3, reducing ferroptosis in H/R-treated cells. This significantly decreased neutrophil infiltration and levels of inflammatory factors in liver tissue, thereby suppressing the inflammatory response and mitigating liver damage (Wu L. et al., 2022).

lncRNA, exceeding 200 nucleotides in length, have crucial roles in various pathways. They influence DNA replication, chromatin organization, gene transcription, and nascent RNA modification in the nucleus, while in the cytoplasm, they regulate mRNA stability and translation, as well as coordinate protein stability and function (Herman et al., 2022). Similar to miRNAs, lncRNA affect gene expression through various mechanisms. As competitive endogenous RNAs, they interact with miRNAs, targeting specific mRNA regions and interfering with gene expression (Shan et al., 2023).lncRNA can function as potential biomarkers for the prognosis and progression of liver fibrosis as well as direct therapeutic targets. Li et al. found that lncRNA FRMD6-AS1 inhibits HSC ferroptosis through negative regulation of the miR-491-5p/USP13 pathway in both in vitro and in vivo models, promoting ECM deposition and advancing liver fibrosis. Knockdown of FRMD6-AS1 significantly increased iron ion, ROS, and MDA levels in activated HSCs while reducing GSH levels and the expression of SLC7A11 and GPX4 proteins, inducing ferroptosis in HSCs, thereby restoring liver tissue structure and reversing liver fibrosis (Li Z. et al., 2024). In patients with chronic hepatitis B (CHB) combined with NAFLD, hypoxia inducible gene domain family member 1A (HIGD1A) was significantly upregulated. Further studies showed that LINC00207 upregulated HIGD1A via the microRNA-761-HIGD1A axis, activating GSH, reducing hepatic ROS levels, and alleviating oxidative stress-induced hepatocyte damage (Zhang H. et al., 2023).Recent research compared serum lncRNA levels between NAFLD patients and healthy controls, revealing significantly elevated lncRNA MALAT1 levels in NAFLD patients. MALAT1 targets the miR-485-5p-MUC1 axis in NAFLD to regulate ferroptosis in hepatocytes and promote the progression of liver fibrosis (Dong et al., 2023). In hepatic ischemia-reperfusion injury, the receptor for activated C kinase 1 (RACK1) directly interacts with AMPKα to regulate its phosphorylation at the Thr172 site, thereby modulating system Xc− activity. This process suppresses lipid peroxidation and ROS accumulation while enhancing glutathione levels, ultimately shielding hepatocytes from ferroptosis triggered by IRI. Moreover, studies have demonstrated that the lncRNA ZFAS1 exacerbates hepatocyte ferroptosis by inhibiting the RACK1/AMPKα signaling pathway (Yang Z. et al., 2024). Dong et al. analyzed gene samples using bioinformatics and identified CYBB as a co-regulated gene in NAFLD, leading to oxidative DNA damage. The taurine upregulated gene 1 (TUG1), a 7.1 kb long lncRNA, may modulate ferroptosis via the CYBB-hsa-miR-196a/b-5p-TUG1 axis, thereby affecting the progression of liver disease (Zhang X. et al., 2023). Additionally, some studies have focused on TUG1’s role in energy metabolism and ferroptosis regulation in liver fibrosis. Zhang et al. indicated that TUG1 is overexpressed in fibrotic liver tissues and HSCs, and it exacerbates liver fibrosis by reducing ferroptosis through enhanced glycolytic metabolism mediated by pyruvate dehydrogenase kinase isozyme 4 (PDK4) (Li MR. et al., 2024). These studies indicate that the differential expression of ferroptosis-related lncRNA in liver fibrosis offers clinical insights for the diagnosis, treatment, and prognosis of this condition.

circRNAs are RNA molecules with a unique circular structure, lacking 5′end caps and 3′end poly A tails, and are structurally more stable than linear RNAs (Li, 2023). They regulate transcription and RNA splicing, bind to mRNAs to influence gene expression, affect the stability and translation of cytoplasmic mRNAs, and interfere with signal transduction (Liu and Chen, 2022).With the advancement of technology and research methods, the regulatory mechanisms of circRNAs in liver fibrosis progression have been increasingly studied. Numerous circRNAs have been identified as significant regulators of liver fibrosis development. Chen et al. used circRNA sequencing (circRNA-seq) to obtain the circRNA expression profile in mouse HSCs, discovering that circFBXW4 was significantly downregulated in liver fibrosis. Overexpression of circFBXW4 inhibited HSC activation and proliferation, reduced collagen deposition, alleviated liver fibrosis progression in mice, and exhibited anti-inflammatory effects. Mechanistically, circFBXW4 inhibited HSC activation and alleviated HF through the miR-18b-3p/FBXW7 axis (Chen et al., 2020). Studies have shown that its downstream target, the ubiquitin ligase FBXW7, exhibited increased binding to RNA-binding protein ZFP36 in mice treated with the ferroptosis inducers erastin and sorafenib. Downregulation of ZFP36 in HSCs activated ferritinophagy, promoted HSC ferroptosis, and countered liver fibrosis (Zhang et al., 2020). HuR, a key RNA-binding protein (RBP), interacts with circDCBLD2 to enhance STUB1 expression and facilitate PARK7 ubiquitination, thereby inducing ferroptosis in HSCs and mitigating liver fibrosis (Wang J. et al., 2024). In a diabetic rat model of liver oxidative damage, upregulation of circ-ITCH was found to promote the Nrf2 signaling pathway, reducing cell oxidative damage caused by ROS (Fu et al., 2024). Upon external stimulation, Nrf2 translocates to the hepatocyte nucleus and activates downstream molecules such as heme oxygenase-1 (HO-1), inhibiting ROS production and thereby preventing ferroptosis and liver injury (Yang et al., 2022).To date, the role of ferroptosis-related circRNA, particularly its association with liver fibrosis, has not been fully elucidated. Therefore, further research is necessary to identify novel therapeutic targets for liver fibrosis.

While ncRNAs exhibit considerable potential in treating liver fibrosis, it is crucial to recognize that research targeting ncRNAs as future therapeutic strategies continues to face numerous challenges. Firstly, despite the growing comprehensiveness of ncRNA-related databases, specialized and integrative resources dedicated to ferroptosis-related ncRNAs in liver fibrosis are still lacking. This scarcity hampers the validation of ferroptosis-related ncRNAs, subsequently restricting the progress and depth of research in this domain and slowing the field’s advancement. Currently, the majority of studies are still in their early stages and predominantly rely on cell and animal models, which partially limits the physiological relevance of the findings. Using the in vitro stimulation model of LX-2 cells as an example, while this model serves as a foundational tool for basic research, its artificially constructed environment cannot fully recapitulate the intricate mechanisms of liver fibrosis in vivo, thus constraining the translational relevance of the findings to clinical practice. Furthermore, within the intricate microenvironment of liver fibrosis, ncRNAs are susceptible to degradation and exhibit poor stability, leading to low in vivo utilization efficiency. Consequently, devising strategies to effectively and precisely deliver ncRNAs to specific liver cell types, such as HSCs or hepatocytes, while preserving their stability in vivo remains a pivotal technical challenge. In conclusion, extensive basic research and well-structured clinical trials are indispensable for promoting the clinical application of emerging ncRNA-based therapies in liver fibrosis treatment. Such efforts are directed toward addressing current limitations and facilitating more efficient therapeutic translation.