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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.
Summary
Hypoxia drives hepatocellular carcinoma (HCC) dedifferentiation via the HIF-2α-RNF126-ABCD3 axis, leading to peroxisome loss. Inhibiting RNF126 restores peroxisomal function, redifferentiating HCC cells and suppressing tumor growth.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Tumor hypoxia in hepatocellular carcinoma (HCC) promotes cell dedifferentiation and metabolic changes.
- This reprogramming undermines normal liver functions and contributes to cancer progression.
Purpose of the Study:
- To identify the molecular mechanisms linking hypoxia to hepatocyte dedifferentiation in HCC.
- To explore RNF126 as a therapeutic target for liver cancer redifferentiation.
Main Methods:
- Investigated the role of E3 ubiquitin ligase RNF126 in hypoxia-induced HCC dedifferentiation.
- Utilized genetic manipulation (RNF126 ablation) and a novel small-molecule inhibitor (D665-1412).
- Assessed peroxisome function, autophagy, lipid metabolism, and hepatocyte differentiation markers.
Main Results:
- Hypoxia induces HIF-2α, which upregulates RNF126, leading to ABCD3 ubiquitination and peroxisome loss via pexophagy.
- RNF126 ablation restored peroxisomal functions and inhibited hypoxic HCC growth.
- The RNF126 inhibitor D665-1412 stabilized peroxisomes, normalized metabolism, and reactivated differentiation markers, suppressing tumor progression.
Conclusions:
- The HIF-2α-RNF126-ABCD3 pathway is a key driver of HCC dedifferentiation.
- Targeting RNF126 with small molecules offers a promising strategy for organelle-targeted redifferentiation therapy in liver cancer.
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