Mitochondrial HMGCS1 mediates cisplatin resistance in cervical cancer through regulation of mitochondrial transcription.

Cisplatin resistance remains a major challenge in the treatment of cervical cancer. Here, we identify 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1), a rate-limiting enzyme in the mevalonate pathway, as a critical regulator of cisplatin resistance through its localization to mitochondria. HMGCS1 preferentially accumulates in the mitochondria of cisplatin-resistant cervical cancer cells, and targeted expression of HMGCS1 to mitochondria, but not to the nucleus or cytosol, is sufficient to confer cisplatin resistance. Mechanistically, mitochondrial HMGCS1 associates with the D-loop region of mitochondrial DNA (mtDNA) and is required for the stable binding of the core transcription machinery components POLRMT, TFAM, and TFB2M. This regulatory function is important for mitochondrial respiratory capacity through its critical role in the transcription of mtDNA-encoded respiratory complex subunits. Genetic depletion or pharmacological inhibition of HMGCS1 disrupts mitochondrial transcription, impairs respiratory function, and re-sensitizes resistant cells to cisplatin. Moreover, combined treatment with cisplatin and inhibitors targeting either HMGCS1 or mitochondrial transcription exhibits synergistic effects against cisplatin-resistant cervical cancer cells. Our findings reveal an unexpected role for HMGCS1 as a non-canonical regulator of mitochondrial transcription and establish the HMGCS1-mitochondrial transcription axis as a promising therapeutic target to overcome cisplatin resistance in cervical cancer.