Hypoxia-responsive PPARGC1A/BAMBI/ACSL5 axis promotes progression and resistance to lenvatinib in hepatocellular
Qiangnu Zhang1,2, Lingfeng Xiong1, Teng Wei3
1Division of Hepatobiliary and Pancreas Surgery, Department of General Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), 518020, Shenzhen, China.
Abstract:
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.
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