Carbonic anhydrase 2 facilitates sorafenib resistance by counteracting MCT4-mediated intracellular pH dysregulation in HCC.

Sorafenib, the targeted therapy for hepatocellular carcinoma (HCC), has been utilized in clinics for over a decade. However, its effectiveness is severely hindered by acquired drug resistance, the mechanisms of which remain largely elusive. In this study, we identify that carbonic anhydrase 2 (CA2) is a key regulator of sorafenib resistance. Mechanistically, sorafenib treatment decreases intracellular pH (pH) by suppressing monocarboxylate transporter 4 (MCT4) expression, while high levels of CA2 counteract MCT4-mediated pH dysregulation upon sorafenib treatment, maintaining pH homeostasis to facilitate cell survival and sorafenib resistance. Targeting CA2 re-sensitizes resistant HCC cells to sorafenib both in vitro and in vivo. Importantly, analysis of clinical samples shows a strong correlation between CA2 expression levels and the therapeutic efficacy of sorafenib in HCC patients. Our findings highlight the significance of CA2 in facilitating sorafenib resistance and propose targeting CA2 as a potential strategy for overcoming sorafenib resistance in HCC patients.