7-Dehydrocholesterol-mediated ferroptosis is governed by glucose availability in pancreatic ductal adenocarcinoma.

7-Dehydrocholesterol (7-DHC) has recently emerged as an endogenous suppressor of lipid peroxidation/ferroptosis; however, its function in nutrient-poor microenvironments remains undefined. Here, we demonstrate that activated c-Myc directly occupies the DHCR7 promoter in pancreatic ductal adenocarcinoma (PDAC) cells, transcriptionally upregulating DHCR7, which converts 7-DHC into cholesterol, thereby fuelling PDAC cell proliferation. Under glucose deprivation, DHCR7 deletion triggers pronounced ferroptosis in PDAC cells, an effect that is sharply attenuated when glucose is supplemented. Mechanistically, DHCR7 inhibition drives 7-DHC accumulation, which plays a dual role: it traps free radicals (anti-ferroptosis) and yet simultaneously depletes the antioxidant pool (pro-ferroptosis), with the net outcome dictated by glucose availability. The antioxidant pool maintained by glucose is required to counteract the pro-peroxidation effects of 7-DHC; once glucose is limited, the radical-trapping-mediated anti-ferroptosis function of 7-DHC becomes negligible. Furthermore, glucose restriction in vitro and a low-glucose diet in vivo both sensitized PDAC cells to DHCR7 inhibition-triggered lipid peroxidation, which allows accelerated cell death or suppressed tumor growth. Collectively, 7-DHC, negatively regulated by the c-Myc/DHCR7 axis, promotes lipid peroxidation and ferroptosis in glucose-deficient PDAC tumors, revealing a metabolic vulnerability that can be exploited for therapy.