Liver fibrosis, characterized by excessive accumulation of extracellular matrix proteins, represents a critical pathological process in the progression of chronic liver disease to cirrhosis and ultimate liver failure (Horn and Tacke, 2024; Kisseleva and Brenner, 2021). The activation of hepatic stellate cells (HSCs) assumes a paramount role within this procedure (Higashi et al., 2017). These cells shift from their primary dormant state, marked by the loss of vitamin A storage, increased proliferation, and the expression of α-smooth muscle actin (α-SMA), which is a hallmark of myofibroblast differentiation (Higashi et al., 2017; Kamm and McCommis, 2022).

During HSC activation, a significant metabolic reprogramming occurs (Du et al., 2018; Horn and Tacke, 2024; Trivedi et al., 2021), characterized by a marked shift from oxidative phosphorylation to aerobic glycolysis. This metabolic adaptation is essential to meet the high energy demands of rapid cell proliferation and collagen production (Ezhilarasan, 2021; Trivedi et al., 2021). The glycolytic switch provides a shorter pathway than oxidative phosphorylation, enabling faster ATP generation and metabolite production to support the increased biosynthetic processes in activated HSCs (DeBerardinis and Thompson, 2012).

The molecular mechanisms underlying this metabolic reprogramming involve multiple pathways, with HIF-1α emerging as a key orchestrator of glycolytic gene expression (Sun et al., 2021; Wang et al., 2024a). HIF-1α stabilization promotes the expression of glucose transporters and glycolytic enzymes (Fan et al., 2020; Sun et al., 2021; Wang et al., 2024a), including PDK1, PKM2, and LDHA. This metabolic signature is commonly induced by various signal transduction pathways, though the precise regulatory mechanisms remain to be fully elucidated.

Among these mediators, high-mobility group box 1 (HMGB1) protein has emerged as a critical player in liver fibrosis pathogenesis. HMGB1, initially described as a nuclear non-histone protein involved in DNA replication and energy homeostasis, can be actively secreted or passively released from injured cells (Chen et al., 2022; Xue et al., 2021). During HSC activation, HMGB1 undergoes translocation from the nucleus to the cytoplasm (Ren et al., 2023) and has been reported to be involved in glycolysis regulation (Kang et al., 2011). Furthermore, HMGB1 mediates the expression of Yes-associated protein (YAP), contributing to aerobic glycolysis in hepatocellular carcinoma cells (Chen et al., 2018). Importantly, HMGB1's regulatory functions appear to extend beyond direct metabolic control through its interactions with other signaling pathways.

The β-catenin pathway, a key component of Wnt signaling (Wang et al., 2024a; Yamaji et al., 2023), plays a crucial role in HSC activation and liver fibrogenesis. Recent evidence suggests a potential physical interaction between HMGB1 and β-catenin (Wang et al., 2020, 2024b), where increased cytoplasmic HMGB1 may interact with β-catenin to enhance its stability and nuclear translocation. The nuclear localization of β-catenin represents a defining step in Wnt pathway activation (Wu et al., 2008), though the mechanisms regulating its nuclear transport remain undefined. Given the critical roles of both HMGB1 and β-catenin in liver fibrosis progression, identifying therapeutic agents that could effectively modulate these pathways has become an important research focus.

Irisin, an exercise-induced myokine, has emerged as a promising therapeutic candidate (Bao et al., 2022; Guo et al., 2023). While initially recognized for its role in promoting brown-like adipocyte development (Zhang et al., 2014) and regulating glucose metabolism (Guo et al., 2023; Polyzos et al., 2018), emerging evidence suggests that irisin may possess anti-fibrotic properties, as seen in doxorubicin-induced (Pan et al., 2021) and myocardial infarction-induced (Li et al., 2024) cardiac fibrosis. However, its specific role and mechanism of action in liver fibrosis, particularly regarding HSC metabolism and the HMGB1/β-catenin signaling pathway, require further investigation.

Therefore, our study sought to investigate the impact of irisin on HSC activation and liver fibrosis, focusing specifically on its influence on cellular energy metabolism through the HMGB1/β-catenin signaling pathway. We propose that irisin may modulate HSC metabolism and activation status by regulating HMGB1 expression and β-catenin activity, thereby affecting the glycolytic reprogramming of activated HSCs. Understanding these mechanisms could provide fresh insights into irisin's therapeutic potential for liver fibrosis treatment.