Targeting CRL4 suppresses chemoresistant ovarian cancer growth by inducing mitophagy.

Chemoresistance has long been the bottleneck of ovarian cancer (OC) prognosis. It has been shown that mitochondria play a crucial role in cell response to chemotherapy and that dysregulated mitochondrial dynamics is intricately linked with diseases like OC, but the underlying mechanisms remain equivocal. Here, we demonstrate a new mechanism where CRL4 CUL4A/DDB1 manipulates OC cell chemoresistance by regulating mitochondrial dynamics and mitophagy. CRL4 CUL4A/DDB1 depletion enhanced mitochondrial fission by upregulating AMPKα Thr172 and MFF Ser172/Ser146 phosphorylation, which in turn recruited DRP1 to mitochondria. CRL4 CUL4A/DDB1 loss stimulated mitophagy through the Parkin-PINK1 pathway to degrade the dysfunctional and fragmented mitochondria. Importantly, CRL4 CUL4A/DDB1 loss inhibited OC cell proliferation, whereas inhibiting autophagy partially reversed this disruption. Our findings provide novel insight into the multifaceted function of the CRL4 E3 ubiquitin ligase complex in regulating mitochondrial fission, mitophagy, and OC chemoresistance. Disruption of CRL4 CUL4A/DDB1 and mitophagy may be a promising therapeutic strategy to overcome chemoresistance in OC.