A long‐acting FGF21 attenuates metabolic dysfunction‐associated steatohepatitis‐related fibrosis by modulating NR4A1‐mediated Ly6C phenotypic switch in macrophages

Background and Purpose Because of the absence of effective therapies for metabolic dysfunction‐associated steatohepatitis (MASH), there is a rising interest in fibroblast growth factor 21 (FGF21) analogues due to their potential anti‐fibrotic activities in MASH treatment. PsTag‐FGF21, a long‐acting FGF21 analogue, has demonstrated promising therapeutic effects in several MASH mouse models. However, its efficacy and mechanism against MASH‐related fibrosis remain less well defined, compared with the specific mechanisms through which FGF21 improves glucose and lipid metabolism. Experimental Approach The effectiveness of PsTag‐FGF21 was evaluated in two MASH‐fibrosis models. Co‐culture systems involving macrophages and hepatic stellate cells (HSCs) were employed for further assessment. Hepatic macrophages were selectively depleted by administering liposome‐encapsulated clodronate via tail vein injections. RNA sequencing and cytokine profiling were conducted to identify key factors involved in macrophage–HSC crosstalk. Key Results We first demonstrated the significant attenuation of hepatic fibrosis by PsTag‐FGF21 in two MASH‐fibrosis models. Furthermore, we highlighted the crucial role of macrophage phenotypic switch in PsTag‐FGF21‐induced HSC deactivation. FGF21 was demonstrated to regulate macrophages in a PsTag‐FGF21‐like manner. NR4A1, a nuclear factor which is notably down‐regulated in human livers with MASH, was identified as a mediator responsible for PsTag‐FGF21‐induced phenotypic switch. Transcriptional control over insulin‐like growth factor 1, a crucial factor in macrophage–HSC crosstalk, was exerted by the intrinsically disordered region domain of NR4A1. Conclusion and Implications Our results have elucidated the previously unclear mechanisms through which PsTag‐FGF21 treats MASH‐related fibrosis and identified NR4A1 as a potential therapeutic target for fibrosis.