新兴证据表明，过氧化物酶体增殖物激活受体γ共激活因子1α（PPARGC1A）参与了肝细胞癌（HCC）的发生。然而，它的详细功能和上下游机制尚未完全理解。在这项研究中，我们利用大规模公共数据集和内部队列证实，PPAGC1A在HCC中表达较低且与恶性预后有关。发现PPAGC1A会损害HCC的进展和对雷伐替尼的敏感性。在机制上，PPAGC1A通过抑制WNT/β-连环蛋白信号通路抑制骨形态发生蛋白和活性素膜束制物（BAMBI）。BAMBI通过调节TGF-β/SMAD信号通路调控了PPARGC1A的功能并调节了ACSL5。PPARGC1A/BAMBI通过控制ACSL5来调节ROS产生和铁死细胞相关的细胞死亡。PPARGC1A/BAMBI/ACSL5轴是缺氧响应的。METTL3和WTAP分别在正常氧和缺氧条件下依赖于m6A-YTHDF2途径沉默了PPARGC1A。二甲双胍通过抑制METL3减少其m6A修饰，从而恢复PPARGC1A表达。在动物模型和患者衍生器官oid中观察到了PPARGC1A/BAMBI/ACSL5的一致功能数据。结论：这些发现提供了对异常PPARGC1A/BAMBI/ACSL5轴在HCC中作用的新见解。而PPARGC1A失调的机制则可通过m6A修饰来解释。而且二甲双胍可能有益于患有PPARGC1A失调的HCC患者。© 2023该作者，专属许可给Springer Nature Limited。

Emerging evidence has indicated that peroxisome proliferator-activated receptor-gamma coactivator-1α (PPARGC1A) is involved in hepatocellular carcinoma (HCC). However, its detailed function and up- and downstream mechanisms are incompletely understood. In this study, we confirmed that PPAGC1A is lowly expressed in HCC and is associated with poor prognosis using large-scale public datasets and in-house cohorts. PPAGC1A was found to impair the progression and sensitivity of HCC to lenvatinib. Mechanistically, PPAGC1A repressed bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) by inhibiting WNT/β-catenin signaling. BAMBI mediated the function of PPARGC1A and regulated ACSL5 through TGF-β/SMAD signaling. PPARGC1A/BAMBI regulated ROS production and ferroptosis-related cell death by controlling ACSL5. PPARGC1A/BAMBI/ACSL5 axis was hypoxia-responsive. METTL3 and WTAP silenced PPARGC1A in an m6A-YTHDF2-dependent way under normoxia and hypoxia, respectively. Metformin restored PPARGC1A expression by reducing its m6A modification via inhibiting METTL3. In animal models and patient-derived organoids, consistent functional data of PPARGC1A/BAMBI/ACSL5 were observed. Conclusions: These findings provide new insights into the role of the aberrant PPARGC1A/BAMBI/ACSL5 axis in HCC. And the mechanism of PPARGC1A dysregulation was explained by m6A modification. Metformin may benefit HCC patients with PPARGC1A dysregulation.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.