Wei, XiaoliXiaoliWeiWu, DongqingDongqingWuLi, JingJingLiWu, MiaomiaoMiaomiaoWuLi, QianhuiQianhuiLiChe, ZhaodiZhaodiCheCheng, XuXuChengCheng, QianyingQianyingChengYin, FanFanYinZhang, HaoHaoZhangWang, XuefuXuefuWangAbtahi, ShabnamShabnamAbtahiZuo, LiLiZuoHang, LeiLeiHangMa, LiliLiliMaWEI-TING KUOLiu, XiaoyingXiaoyingLiuTurner, Jerrold RJerrold RTurnerWang, HuaHuaWangXiao, JiaJiaXiaoWang, FeiFeiWang2024-12-192024-12-192024-10-01https://scholars.lib.ntu.edu.tw/handle/123456789/724098Macrophage-mediated inflammation has been implicated in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH); however, the immunometabolic program underlying the regulation of macrophage activation remains unclear. Beta-arrestin 2, a multifunctional adaptor protein, is highly expressed in bone marrow tissues and macrophages and is involved in metabolism disorders. Here, we observed that β-arrestin 2 expression was significantly increased in the liver macrophages and circulating monocytes of patients with MASH compared with healthy controls and positively correlated with the severity of metabolic dysfunction-associated steatotic liver disease (MASLD). Global or myeloid Arrb2 deficiency prevented the development of MASH in mice. Further study showed that β-arrestin 2 acted as an adaptor protein and promoted ubiquitination of immune responsive gene 1 (IRG1) to prevent increased itaconate production in macrophages, which resulted in enhanced succinate dehydrogenase activity, thereby promoting the release of mitochondrial reactive oxygen species and M1 polarization. Myeloid β-arrestin 2 depletion may be a potential approach for MASH.enIRG1MASLDitaconatemacrophage polarizationmetabolic reprogrammingβ-arrestin 2[SDGs]SDG2journal article10.1016/j.cmet.2024.08.01039305895