Genome-wide CRISPRi screen identifies basigin loss as protective in cardiac hypoxia

ABSTRACT Cardiac function depends on continuous oxidative metabolism, rendering cardiomyocytes highly vulnerable to oxygen deprivation. Here, we performed a genome-wide CRISPR interference (CRISPRi) screen in human iPSC-derived cardiomyocytes to identify genes that modulate survival during chronic hypoxia. This screen revealed that knockdown of basigin (BSG), a chaperone for the monocarboxylate transporters MCT1 and MCT4, confers robust protection. Canonically, hypoxic cells suppress pyruvate dehydrogenase (PDH) activity to reduce the oxidation of major fuel sources, thereby limiting TCA cycle flux, lowering oxygen consumption, and minimizing reactive oxygen species generated by an overly reduced electron transport chain (ETC). In contrast, we found that BSG inhibition reverses this response, prioritizing ATP maintenance during hypoxia and enhancing cardiomyocyte survival. Mechanistically, BSG loss restricts lactate efflux, leading to decreased PDH phosphorylation and increased glucose uptake for oxidation. Consistent with this, ETC subunits are more essential under hypoxia, highlighting cardiomyocytes’ unusual reliance on aerobic ATP production even when oxygen is limited. These findings challenge prevailing models of hypoxic adaptation by revealing cardiomyocyte-specific bioenergetic requirements and motivating future therapeutic efforts.