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RNF126 is a peroxisomal fate switch enabling redifferentiation therapy in hepatocellular carcinoma
Qi Su1,2, Yichun Yang1,2, Jiayan Ren1,2
1School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China.
Abstract:
Tumor hypoxia promotes dedifferentiation and metabolic reprogramming in hepatocellular carcinoma (HCC), undermining normal liver functions. Here, we identify the E3 ubiquitin ligase RNF126 as a hypoxia-inducible "peroxisomal fate" switch that links the hypoxic microenvironment to loss of hepatocyte differentiation. Under hypoxia, HIF-2α drives RNF126 expression, which in turn ubiquitinates the peroxisomal membrane transporter ABCD3, triggering selective peroxisome autophagy (pexophagy) and depletion of peroxisomes. This organelle loss ablates very-long-chain fatty acid β-oxidation and hydrogen peroxide detoxification, erasing key hepatocyte differentiation features. We show that genetic RNF126 ablation restores peroxisomal functions and impairs hypoxic HCC growth. Leveraging these insights, we developed a small-molecule RNF126 inhibitor, D665-1412, which selectively blocks hypoxia-induced pexophagy. D665-1412 treatment stabilizes peroxisomes, normalizes lipid metabolism, and reactivates hepatocytic differentiation markers, thereby "redifferentiating" HCC cells and suppressing tumor progression in vitro and in vivo. Our findings establish the HIF-2α-RNF126-ABCD3 axis as a driver of HCC dedifferentiation and present organelle-targeted redifferentiation therapy as a promising approach for liver cancer.
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