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PsTag\u2010FGF21, a long\u2010acting FGF21 analogue, has demonstrated promising therapeutic effects in several MASH mouse models. However, its efficacy and mechanism against MASH\u2010related fibrosis remain less well defined, compared with the specific mechanisms through which FGF21 improves glucose and lipid metabolism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>The effectiveness of PsTag\u2010FGF21 was evaluated in two MASH\u2010fibrosis models. Co\u2010culture systems involving macrophages and hepatic stellate cells (HSCs) were employed for further assessment. Hepatic macrophages were selectively depleted by administering liposome\u2010encapsulated clodronate via tail vein injections. RNA sequencing and cytokine profiling were conducted to identify key factors involved in macrophage\u2013HSC crosstalk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>We first demonstrated the significant attenuation of hepatic fibrosis by PsTag\u2010FGF21 in two MASH\u2010fibrosis models. Furthermore, we highlighted the crucial role of macrophage phenotypic switch in PsTag\u2010FGF21\u2010induced HSC deactivation. FGF21 was demonstrated to regulate macrophages in a PsTag\u2010FGF21\u2010like manner. NR4A1, a nuclear factor which is notably down\u2010regulated in human livers with MASH, was identified as a mediator responsible for PsTag\u2010FGF21\u2010induced phenotypic switch. Transcriptional control over insulin\u2010like growth factor 1, a crucial factor in macrophage\u2013HSC crosstalk, was exerted by the intrinsically disordered region domain of NR4A1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>Our results have elucidated the previously unclear mechanisms through which PsTag\u2010FGF21 treats MASH\u2010related fibrosis and identified NR4A1 as a potential therapeutic target for fibrosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.16378","type":"journal-article","created":{"date-parts":[[2024,4,28]],"date-time":"2024-04-28T21:44:16Z","timestamp":1714340656000},"page":"2923-2946","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["A long\u2010acting FGF21 attenuates metabolic dysfunction\u2010associated steatohepatitis\u2010related 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