IL-6, a critical inducer of B-cell immunoglobulin, is predominantly expressed in lymphocytes, hepatocytes, epithelial cells, and macrophages. It is swiftly upregulated in response to infection or tissue injury, thereby facilitating the body’s defense mechanisms through the mediation of acute-phase responses, immune responses, and hematopoietic regulation (13). Furthermore, IL-6 is involved in systemic metabolic regulation, and can initiate inflammatory cascades. Empirical research has substantiated its pivotal role in various immune regulatory pathways (14). Additionally, IL-6 is typically recognized by pattern recognition receptors on immune cells at sites of infection, mediating the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells(NF-κB) signaling pathway, which in turn enhances the expression of inflammatory factors, including IL-6 itself. Tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) enhance IL-6 production by activating transcription factors, leading to a self-sustaining positive feedback loop in the inflammatory process (13).

IL-11, a cytokine secreted by fibroblasts, supports the maintenance of IL-6-dependent hematopoietic cell lines primarily through its interaction with the gp130 and IL-11 receptor complex. Additionally, IL-11 plays a crucial role in modulating inflammatory responses by exerting significant anti-inflammatory effects (15).

IL-27 is predominantly secreted by antigen-presenting cells following stimulation of pattern recognition receptors, facilitating the proliferation of naive CD4⁺T cells and the differentiation (16). into the Th1 subtype. Research suggests that IL-27 plays a crucial role in regulating the balance between pro-inflammatory and anti-inflammatory, responses, modulating immune responses, and influencing the tumor microenvironment (17).

OSM, as a multifunctional cytokine, is synthesized by a diverse array of cell types, like activated monocytes/macrophages, T cells, dendritic cells, and neutrophils (18). Primarily serving as a growth regulator, OSM demonstrates a wide range of biological functions, particularly in the contexts of inflammation, liver fibrosis, and oncological conditions (19, 20). In the realm of inflammatory diseases, OSM is capable of activating the NF-κB and JAK/STAT3 signaling pathways, which in turn stimulate cell proliferation and the secretion of inflammatory mediators, thereby facilitating the advancement of chronic inflammation (21).

IL-31, a newly identified pro-inflammatory cytokine, is predominantly expressed in activated helper T cell populations, with a particular emphasis on the Th2 cell subset (22). Upon interacting with its specific receptor, IL-31 activates the JAK/STAT, Phosphoinositide 3-kinase/Ak strain Transforming (PI3K/AKT), and Mitogen-Activated Protein Kinase(MAPK) signaling pathways, thereby influencing a variety of immune and non-immune cells to contribute to immune responses, inflammatory diseases, and allergic reactions (23). Research shows that IL-31 can trigger the overexpression of pro-inflammatory cytokines like IL-6 and other chemokines by activating extracellular signal-regulated kinases, thereby worsening inflammation (24).

Beyond its function in modulating the equilibrium between pro-inflammatory and anti-inflammatory responses, IL-27 also plays a crucial role in enhancing thermogenesis, preventing diet-induced obesity, and ameliorating insulin resistance. This is accomplished through its direct interaction with adipocytes, where it activates the p38 Mitogen-activated protein kinase- Peroxisome proliferator-activated receptor γ coactivator-1α (p38 MAPK-PGC-1α) signaling pathway and induces the expression of uncoupling protein 1 (UCP1), thereby facilitating thermogenesis (25).

LIF is recognized as the most versatile member of the IL-6 cytokine family (26), demonstrating biological activity across a wide range of tissues (27). Prior research has substantiated its roles, notably as a human hepatocyte growth factor and as an inhibitor of differentiation in mouse embryonic stem cells. Further investigations have elucidated its capacity to inhibit lipoprotein lipase derived from melanoma, thereby modulating systemic lipid metabolism through the suppression of lipoprotein lipase activity (28).

CNTF is among the most extensively investigated neuroprotective nutritional factors, originally identified for its role in enhancing the survival and growth of ciliary ganglion cells. It is expressed in retinal cells, neurons, and adipocytes (29). Under normal conditions, CNTF helps regulate lipid metabolism by reducing food intake and increasing energy expenditure through central nervous system metabolic pathways (30, 31).

CLCF1 not only exhibits the typical biological characteristics of the IL-6 family but also significantly stimulates the proliferation of B cells (32), primarily expressed in lymphoid tissues and involved in immune regulation (33). Recent studies have identified its expression in adipocytes and hepatocytes, where CLCF1 engages in an autocrine signaling pathway in brown adipose tissue. binds to the gp130/CNTFR/LIFR receptor complex to activate downstream JAK/STAT3 signal transduction, thereby inhibiting the expression of PGC-1α and PGC-1β, ultimately leading to a reduction in adipocyte thermogenesis (30). Under conditions of metabolic stress, the expression of this factor is markedly upregulated in both adipose tissue and the liver. Research indicates that while CLCF1 inhibits thermogenesis in adipocytes, it promotes liver metabolism, suggesting that CLCF1 plays a dual regulatory role in maintaining tissue-specific homeostasis (30, 34).

Research shows that IL-11, part of the IL-6 cytokine family, has anti-inflammatory effects but also plays a key role in autoimmune disease progression, bone metabolism regulation, fibrosis, and aging (35, 36). IL-11 influences key fibrotic-related genes downstream of fibrotic mediators like TGFβ1, thereby promoting the fibrotic pathological process in tissues (37).

In the context of liver diseases, OSM enhances the expression of tissue inhibitor of metalloproteinases 1 (TIMP1), suppresses fibrinolytic activity in hepatic stellate cells, and facilitates the proliferation of myofibroblasts, thereby contributing to the pathogenesis of liver fibrosis (38).

CTF1 is multifunctional, initially noted for cardioprotection, and widely expressed in the liver, kidneys, lungs, and skeletal muscle (39, 40). Beyond its role in myocardial protection (41), recent investigations have revealed that CTF1 functions as an autophagy activator in fibroblasts and tumor-associated fibroblasts. This is accomplished through the induction of STAT3 phosphorylation and nuclear translocation, which activates the transcription of autophagy-related proteins. Furthermore, CTF1synergizes with the activation of the Adenosine Monophosphate-activated Protein Kinase-Unc-51 Like Kinase 1(AMPK/ULK1) signaling axis, leading to fibroblast activation and the progression of fibrotic pathology (42).

The expression levels of IL-11 exhibit an increasing trend with advancing age.IL-11 plays a regulatory role in age-associated pathological processes at both the cellular and tissue levels through the sequential activation of the Extracellular signal-Regulated kinase-AMP-Activated Protein Kinase-mechanistic Target of Rapamycin Complex1 (ERK-AMPK-mTORC1) and JAK/STAT3 signaling pathways, ultimately contributing to the induction of aging (43, 44).

Within the realm of tumor pathology, OSM has been recognized as a pro-tumorigenic factor. Research shows that OSM promotes tumor invasion and metastasis by increasing matrix metalloproteinase (MMP) expression and activating the JAK/STAT3 pathway (45).

In hepatocellular carcinoma (HCC), CLCF1 enhances CXCL6 and TGF-β expression through the Akt/ERK1/2-STAT3 pathway, promoting stem cell traits and self-renewal in cancer cells (46) ( Table 1 ).

MAFLD is defined by an abnormal buildup of fat in the liver, without other causes like heavy alcohol use. Histologically, MAFLD is classified into NAFL and NASH, with the latter representing the primary progression of MAFLD (47). The difference between NAFL and NASH is based on the pathological features observed in liver histology. NAFL is predominantly marked by steatosis, accompanied by mild lobular inflammation and hepatocellular ballooning, with or without perisinusoidal fibrosis (48). In contrast, NASH is characterized by a disease process involving inflammation and hepatocellular injury, typically associated with hepatocellular fibrosis, which can develop into cirrhosis and eventually lead to hepatocellular carcinoma (49).

Biomarkers for MAFLD are integral to three primary domains: (1) quantification of hepatic fat content for diagnostic purposes; (2) evaluation of disease severity, specifically the extent of inflammation and fibrosis; and (3) monitoring temporal changes in hepatic stiffness (50). Presently, the predominant methodologies employed for MAFLD diagnosis encompass serological assays and imaging modalities. Serological assessments usually measure liver function indicators, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) to evaluate MAFLD progression. Elevated ALT and AST levels are not definitive indicators of MAFLD, as they can remain normal in some patients, particularly early in the disease or before significant progression (51–53). As MAFLD becomes more common and diagnostic methods improve, imaging techniques like ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) can now noninvasively detect steatosis. However, a liver biopsy is still needed for a definitive NASH diagnosis, as it assesses liver tissue for fat accumulation and fibrosis progression (54).

The exact cause of MAFLD remains unclear, but it may be linked to insulin resistance(IR), oxidative stress, adipokines, and gut microbiota imbalance (3).

The liver is the body’s primary metabolic hub, fat digestion and absorption, coagulation factor synthesis, bile production, and hormone regulation (55). The pathological progression of MAFLD is characterized by a “three-strike” process: steatosis, lipotoxicity, and inflammation (56). Research indicates that individuals with MAFLD often adhere to unhealthy dietary patterns, marked by a high consumption of diets rich in fats or sugars. This dietary behavior impacts the synthesis and uptake of hepatic free fatty acids (FFAs), resulting in an excessive accumulation of FFAs (57). Furthermore, insulin resistance (IR) in adipose tissue causes peripheral lipolysis and substantial mobilization of FFA from adipocytes overloaded with fat to the liver, culminating in hepatic FFA accumulation (3). The accumulation of lipids within hepatocytes represents the “first strike” in the pathogenesis of MAFLD. In individuals with severe MAFLD, hepatic function significantly declines as the extent of fatty liver severity rises, resulting in hepatic IR and elevating the risk of concomitant type 2 diabetes mellitus (58). Prolonged fat accumulation stimulates the enhanced production of pro-inflammatory cytokines, for example, TNF-α, IL-6, and IL-1β, via activation of the NF-κB signaling pathway. These inflammatory cytokines facilitate the recruitment and activation of Kupffer cells, thereby mediating inflammation in NASH (59). In NASH, FFAs serve as critical mediators of lipotoxicity, facilitating the transition of the liver from basic fat accumulation to steatoinflammation (60). The inflammatory response and hepatocyte ballooning associated with steatosis contribute to hepatocyte apoptosis. Concurrently, the activation of hepatic stellate cells (HSCs), which originate from the extracellular matrix, results in the secretion of collagen fibers, thereby initiating fibrosis and hepatic parenchymal dysfunction. This process subsequently advances to hepatic fibrosis (61). It is well-established that the liver possesses a robust capacity for self-repair. However, in instances where pathogenic factors are not entirely eradicated, this self-repair capability may exacerbate hepatic fibrosis, significantly compromising the liver’s original architecture. This deterioration can lead to the progression of cirrhosis, particularly as the severity of hepatic fibrosis increases, ultimately impairing liver function and advancing to end-stage liver disease (62, 63).

Lipid metabolism balance is crucial for energy supply, cell membrane integrity, and signaling. Its disruption is associated with metabolic disorders like obesity, atherosclerosis, and MAFLD (69). Fatty liver forms due to disrupted liver lipid metabolism and excessive triglyceride buildup in liver cells. This can be caused by increased fatty acid uptake and synthesis, decreased lipolysis, and reduced triglyceride or very low-density lipoprotein (VLDL) release (69). Hepatic lipids are regulated by complex interactions between external and internal factors, involving various cell types and multiple cytokines (70). The IL-6 family, including IL-6, IL-11, LIF, and OSM, plays a key role in MAFLD by disrupting lipid metabolism and causing abnormal lipid buildup.

When it comes to the regulation of lipid metabolism, acetyl-coenzyme A (CoA) carboxylase (ACC) plays a pivotal role by catalyzing the conversion of acetyl-CoA to malonyl-CoA. This reaction facilitates the incorporation of carbon into the de novo synthesis of fatty acids and serves as a key regulatory point in cellular lipid metabolism. ACC is essential for shifting from early lipid metabolism to glycolysis and remodeling in macrophages (71). Studies have demonstrated that upregulation of IL-6 expression leads to increased protein expression levels of sterol regulatory element-binding protein 1 (SREBP-1), fatty acid synthase (FASN), and ACC. This upregulation boosts protein synthesis and inhibits their expression in adipocytes, promoting fat production and resulting in increased lipid accumulation in non-adipose tissues such as the liver and muscle (72). Furthermore, IL-6 increases the serum expression levels of FAA, resulting in disruptions to the lipid metabolism system and inducing IR, thereby exacerbating liver injury (72, 73). Research shows that IL-6 from fat tissue influences liver insulin resistance by increasing Suppressor of Cytokine Signaling 3 (SOCS3) levels (73). SOCS3 overexpression in the liver leads to insulin resistance and increases SREBP-1 expression, which regulates fatty acid synthesis (74). These results suggest that IL-6 plays a role in fat production and insulin resistance in non-adipose tissues.

Hepatocytes exhibit elevated expression of IL11RA and secrete IL-11 in response to the accumulation of lipids. The autocrine activity of IL-11 is facilitated by reactive oxygen species (ROS) derived from NADPH Oxidase 4 (NOX4), as well as by the activation of Extracellular Signal-Regulated Kinase (ERK), c-Jun N-terminal Kinase (JNK), and cysteine-aspartate-specific kinase (CASK). This signaling cascade, involving ERK, JNK, and Cysteine Aspartate-Specific Protease 3 (caspase-3), results in compromised mitochondrial function and diminished fatty acid oxidation, ultimately impacting hepatocyte viability (75). Excess lipids in liver cells trigger IL-11 secretion, enhancing its autocrine action, which then upregulates NOX4 and boosts ROS production. This sequence of events impairs the oxidative capacity of hepatocyte mitochondria and disrupts fatty acid metabolism, culminating in the development of steatosis (75). New findings suggest have elucidated the mechanism by which IL-11 contributes to the progression from MAFLD to NASH. By developing a model of lipotoxicity-driven disease progression, researchers have demonstrated that lipid-accumulating hepatocytes secrete IL-11. This secretion induces metabolic dysfunction and hepatocyte cell death through an autocrine effect, while also activating HSCs and other hepatocytes via a paracrine mechanism (73). IL-11 triggers lipotoxic injury via hepatocyte-specific cis-signaling, influencing metabolic balance and offering insights into the progression from MAFLD to NASH (75).

Tumor tissues express high levels of LIF due to its complex role and specific action on cells and tissues. This molecule, secreted by tumors, promotes fat breakdown in cancerous areas, causing weight loss (76).LIF is crucial for regulating triglyceride (TG) metabolism in the liver, essential for maintaining lipid balance. LIF expression levels are significantly correlated with the pathological progression of MAFLD. At normal expression levels, LIF exerts a protective effect on hepatic lipid homeostasis by initiating the STAT3 signaling pathway, which inhibits the expression of SREBP-1c, thereby reducing TG accumulation in the liver (77). Conversely, LIF overexpression disrupts lipid homeostasis and diminishes hepatic de novo lipogenesis. Overexpression activates STAT3 signaling in hepatocytes, downregulating Peroxisome Proliferator-Activated Receptor Alpha (PPARα), reducing lipogenesis, and disrupting liver lipid balance (77, 78).

OSM serves multiple functions in hepatic lipid metabolism. Microglia and macrophages express it in response to prostaglandin E2 (PGE2) through a signaling pathway dependent on cAMP/PKA (79). In hepatocytes, OSM expression inhibits carnitine palmitoyltransferase-1 (CPT1), thereby preventing the entry of fatty acids into mitochondria for β-oxidation, which leads to their intracellular accumulation (80). Furthermore, OSM induces the expression of apolipoprotein B (ApoB), which, in conjunction with PGE2, inhibits the expression of microsomal transfer proteins. This inhibition results in impaired VLDL expression, further exacerbating triglyceride accumulation in the liver (81), a process intricately linked to the development of IR (80).

Furthermore, OSM facilitates the transition from fatty acid oxidation to Lipid buildup in hepatocytes, which is caused by the elevated expression of SOCS3 (82–84). Importantly, adipose tissue macrophages(ATMs) are pivotal in metabolic inflammation, serving as a primary source of OSMβ. M1 macrophages infiltrate adipose tissue via a chemokine-dependent mechanism, and their secretion of inflammatory mediators impairs insulin signaling (85). This impairment exacerbates hepatic gluconeogenesis when insulin signaling is entirely disrupted in the liver.

When key insulin signaling components that suppress liver gluconeogenesis are impaired, the remaining functional pathways promote liver lipogenesis (86). Insulin boosts the expression of SREBF-1, FAS, and SCD-1, increasing liver fatty acid production, which may lead to more fat accumulation in the liver (87). This adipose tissue inflammation within the liver establishes a self-perpetuating cycle with dysregulated hepatic lipid metabolism, culminating in the onset of metabolic dysregulation (85).

Insulin, a protein hormone produced by the β-cells of the pancreatic islets, primarily functions to lower blood glucose levels, promote the synthesis of glycogen, lipids, and proteins, and regulate glucose and lipid metabolism (88). When insulin action is impaired, the liver cannot effectively lower blood sugar, leading to insulin resistance. This results in reduced glycogen synthesis, increased gluconeogenesis, higher blood glucose levels, more lipid production, and ultimately, fat buildup in the liver (89).

Excess fatty acid production overwhelms fat tissue storage, causing endocrine dysfunction and abnormal fat buildup. This leads to lipotoxicity, which triggers liver inflammation and insulin resistance (90). Lipotoxicity facilitates the release of inflammatory mediators and exacerbates IR, while also intensifying lipolysis and further elevating FFA levels. The interaction between lipotoxicity, insulin resistance, and inflammation creates a harmful cycle that advances MAFLD to more severe stages. Saturated fatty acids(SFAs) activate IκB kinase-β(IKK-β), a key kinase in the NF-κB pathway, significantly increasing the production of the pro-inflammatory cytokine IL-6 (91). IL-6 subsequently activates the JNK signaling pathway and inhibits the insulin secretory function induced by IL-1. However, chronic elevation of IL-6 disrupts glucose homeostasis and fosters the advancement of IR (92). Besides the effects of irregular lipid metabolism, inflammation plays a significant role in contributing to IR. Specifically, IL-6 boosts the expression of SOCS3 by activating dual signaling pathways mediated by STAT3 and NF-κB (80). SOCS3 is considered an essential mediator in the negative regulation of insulin signaling pathways by inflammatory cytokines (93). It exerts its effects by attaching to insulin receptors and inhibiting the phosphorylation of insulin receptor substrate 1 (IRS-1) and IRS-2, thereby reducing insulin-dependent glucose transport (94). This inhibitory effect is particularly pronounced in the liver, leading to impaired hepatic insulin receptor signaling and decreased systemic insulin sensitivity.

The inhibition of adipocyte differentiation and the expansion of adipose tissue have been identified as significant pathogenic factors in IR (95). OSM, an inhibitor of adipogenesis, negatively impacts metabolic homeostasis by affecting metabolic processes through two pathways. It directly contributes to insulin resistance by inhibiting adipogenesis (96). Secondly, OSM plays a pivotal role in insulin signaling by modulating ATM polarization. Research indicates that in mice deficient in the OSM receptor β-subunit (OSMRβ-/-), ATMs are polarized towards the M1 phenotype, resulting in heightened inflammation within fat tissue (97). This polarization leads M1 macrophages to infiltrate adipose tissue through a chemokine-dependent process, releasing pro-inflammatory cytokines such as TNF-α and IL-1β, which inhibit insulin signaling and worsen IR (85).

In hepatic metabolic regulation, PGE2 from Kupffer cells may affect liver insulin resistance by disrupting SOCS3, which decreases insulin-driven glucose use (80). Secondly, PGE2 may modulate insulin resistance by influencing cytokine production in liver nonparenchymal cells (80). Specifically, PGE2 induces the secretion of the cytokine OSM by Kupffer cells, which in turn activates SOCS3 expression in hepatocytes via the STAT3 signaling pathway (80). Importantly, SOCS3 not only serves as a downstream target of the STAT3 signaling pathway but also further impairs insulin signaling by inhibiting Akt phosphorylation and glucokinase activity. This dual mechanism ultimately exacerbates insulin resistance (80).

IL-6, IL-11, and OSM from the IL-6 cytokine family exhibit strong pro-inflammatory effects in the liver, particularly during the NASH stage. They enhance inflammatory signaling, leading to the release of pro-inflammatory mediators and activation of Kupffer cells, which exacerbates liver inflammation (6, 98, 99).

IL-6 plays a bifunctional role in hepatic pathology. Initial research indicated that IL-6 facilitates liver regeneration following partial hepatectomy (100). Conversely, IL-6 demonstrates pro-inflammatory characteristics during chronic liver injury (101). The onset and persistence of liver inflammation play key roles in the pathogenesis of NASH (102), a condition distinctly marked by hepatic inflammation and steatosis. Moreover, in patients, higher plasma IL-6 levels are associated with more severe NASH. The underlying mechanism involves several signaling pathways: (1) the classical IL-6/IL-6 receptor (IL-6R) interaction induces gp130 dimerization, subsequently activating the downstream STAT3 signaling pathway through JAK phosphorylation (103).

Specifically, IL-6 impedes IR signaling and modulates both the acute phase response and chronic inflammation by inhibiting the SOCS-3-SREBP-1C-fatty acyl coenzyme A (FA-CoA) pathway, which subsequently suppresses IR signaling (6). Concurrently, IL-6 promotes Kupffer cells activation and secretion of pro-inflammatory cytokines, including tumor necrosis TNF-α and IL-1β, thereby enhancing the inflammatory response in hepatocytes and deterioration of the NASH (104). Secondly, phosphodiesterase 4 (PDE4) aggravates the inflammatory response in NASH by degrading cyclic adenosine monophosphate (cAMP) and disrupting intracellular signaling, which further elevates IL-6 expression levels (105). Thirdly, the core of inflammatory signaling is characterized by the reversible phosphorylation of protein regulators and effector molecules, particularly MAPK (106). Among these, p38α plays a pivotal role, with macrophage p38α being instrumental in promoting hepatic steatosis and the inflammatory response by inducing the secretion of the pro-inflammatory cytokine IL-6 through the polarization of M1 macrophages.

IL-11 is predominantly synthesized by fibroblasts, and prior research has identified its involvement in processes such as pro-platelet production, suppression of inflammatory responses, and mucosal protection (107). In models of hepatic ischemia/reperfusion (I/R), IL-11 demonstrates anti-inflammatory properties and hepatoprotective effects (108). However, recent investigations have indicated that IL-11 adversely impacts hepatocyte function following severe liver injury, as evidenced by the promotion of hepatocyte steatosis and accelerated disease progression (109). Additional studies have shown that the stimulation of transforming growth TGFβ1 induces the production of IL-11 receptor alpha (IL-11RA) in hepatocytes, thereby activating the IL-11 signaling pathway (109). This signaling pathway not only exhibits cytotoxic effects but also enhances the infiltration of inflammatory cells and promotes the release of pro-inflammatory cytokines via the inflammatory signaling pathway, initiating an inflammatory cascade that ultimately drives disease progression (109).

Liver fibrosis is a pathological condition marked by an imbalance in the production and breakdown of extracellular matrix components (110). This condition begins when injured hepatocytes release chemokines, attracting inflammatory cells and amplifying local inflammation (111). The coordinated activation of liver stellate cells, myofibroblasts, cholangiocytes, and macrophages contributes to the excessive buildup of harmful extracellular matrix components, driving liver fibrosis progression (112). Early-stage hepatic fibrosis can be reversed as part of the body’s repair process, but without timely treatment, it may progress to irreversible cirrhosis (113). This progression increases the risk of portal hypertension, hepatic failure, and HCC, leading to organ failure and death (114, 115).

Damage to hepatocytes leads to a rise in inflammatory cell infiltration and the release of pro-inflammatory cytokines, which are crucial in initiating liver fibrosis (111). IL-6, a key inflammatory mediator, activates the STAT3 pathway, worsening hepatocyte damage and significantly promoting HSC activation (116). HSCs, which are the primary effector cells in the inflammatory response and liver fibrosis, maintain a quiescent phenotype under normal physiological conditions but undergo a multidimensionally regulated activation process (117). Upon activation, HSCs transform into myofibroblast-like cells through multiple signaling pathways. Besides the usual STAT3 pathway, IL-6 aids this conversion by activating the MAPK and JAK/STAT pathways, particularly via p38 and ERK (118). Recent research shows that Fendrr, a long non-coding RNA, binds to STAT2 to enhance IL-6 expression, stimulating HSC via paracrine signaling and promoting liver fibrosis progression (117).

IL-11 plays a crucial role in MAFLD progression by promoting inflammation and fibrosis through a multicellular mechanism. It interacts with HSCs via the IL-11RA receptor in a paracrine or autocrine manner. Hepatocytes release IL-11 when stimulated by TGFβ1, which then activates HSCs paracrinally (75). Moreover, HSCs release significant IL-11 levels when exposed to pathological stimuli (109). IL-11’s pro-fibrotic effects are mainly facilitated by activation of the HSC/extracellular signal-regulated kinase (ERK) pathway, a process that facilitates the conversion of HSCs into myofibroblasts and promotes the secretion of collagen and other matrix proteins, thereby directly contributing to fibrosis (119).

OSM, a cytokine released by Kupffer cells, shows varying expression in the liver. In a healthy liver, it aids development and regeneration, but in disease states, it promotes fibrosis (120). Research shows that OSM aids hepatocyte function recovery by inducing TIMP1 expression in acute liver injury but has pro-fibrotic effects in chronic liver disease (121). OSM enhances the articulation of TIMP1 and conversion of growth TGF-β through the activation of the JAK-STAT3 signaling pathway. TIMP1 subsequently inhibits fibrinolysis in HSCs and promotes fibrosis by inducing the expression of type I collagen (122). Furthermore, OSM has been observed to stimulate hepatic fibroblast migration and overexpression of pro-fibrotic factors in NAFLD (121). OSM facilitates fibrotic progression primarily through a synergistic mechanism involving the regulation of hepatic macrophages (HMs) and HSCs. This is evidenced by the upregulation of pro-fibrotic mediators like TGF-β and platelet-derived growth factor (PDGF) in HMs. Additionally, Fibrosis is indirectly influenced by OSM through the upregulation of TGF-β, PDGF, collagen, and TIMP1 in HSCs and myofibroblasts (MFs) (121). These findings indicate that OSM can induce hepatic fibrosis by modulating the interaction between HSCs and HMs and by promoting the migration of hepatic myofibroblasts (121) ( Figure 1 ).