The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid β-oxidation and induces monocyte chemotaxis via C–C motif chemokine ligand 2. In male mice with diet-induced MASH, targeting oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lowers steatohepatitis and fibrosis by inducing PPARα-driven fatty acid β-oxidation and suppressing monocyte chemotaxis, nuclear factor-κB and transforming growth factor-β targets. These findings highlight hepatic oxalate overproduction as a target for the treatment of MASH.

代谢功能障碍相关脂肪性肝炎 （MASH） 的发病率呈上升趋势，由于可用的药物治疗有限，迫切需要确定新的代谢靶点。草酸盐是由肝乳酸脱氢酶 （LDHA） 由乙醛酸盐产生的末端代谢物。肝脏特异性丙氨酸-乙醛酸转氨酶 （AGXT） 对乙醛酸进行解毒，防止草酸盐积累。在这里，我们表明 AGXT 受到抑制，LDHA 在 MASH 患者和小鼠的肝脏中被激活，导致草酸盐过量产生。反过来，草酸盐通过抑制过氧化物酶体增殖物激活受体α （PPARα） 转录和脂肪酸β氧化促进肝细胞脂肪变性，并通过 C-C 基序趋化因子配体 2 诱导单核细胞趋化性。在饮食诱导的 MASH 雄性小鼠中，通过肝细胞特异性 AGXT 过表达或 LDHA 的药理学抑制来靶向草酸盐过量，通过诱导 PPARα 驱动的脂肪酸β氧化和抑制单核细胞趋化性、核因子-κB 和转化生长因子-β靶标，有效降低脂肪性肝炎和纤维化。这些发现强调了肝脏草酸盐过量产生是治疗 MASH 的靶点。