Autophagic flux inhibition potentiates disulfidptosis susceptibility in human hepatocellular carcinoma

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Abstract Disulfidptosis is a newly recognized form of non-classical cell death, characterized by the abnormal accumulation of disulfide bonds and the collapse of the cytoskeleton. Nevertheless, the regulatory mechanisms governing this process are not fully understood. Although autophagy is a crucial cellular process necessary for maintaining homeostasis, its influence on the susceptibility to disulfidptosis and the associated mechanisms is currently unknown. This study primarily explored the interaction between autophagy and disulfidptosis in hepatocellular carcinoma (HCC) cells. In this research, both a pharmacological targeting model and a gene-modified model were established for functional and mechanistic assays. The impact of autophagy on disulfidptosis was assessed both in vitro and in vivo. Our findings revealed that the inhibition of autophagic flux significantly sensitized HCC cells to disulfidptosis through metabolic reprogramming, where the suppression of autophagy resulted in the downregulation of glucose-6-phosphate dehydrogenase (G6PD) and impaired the generation of nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) and glutathione (GSH), which are critical for maintaining redox balance during disulfidptosis. Furthermore, the inhibition of autophagy also led to the suppression of mitophagy and mitochondrial dysfunction, which may further contribute to metabolic disruptions. Meanwhile, we identified endoplasmic reticulum (ER) stress as an autophagy-dependent regulator of disulfidptosis, thereby establishing a comprehensive ER stress-autophagy-disulfidptosis axis. More importantly, we repurposed the clinical drug clofazimine as a novel disruptor of the equilibrium between ER stress and autophagy, which significantly enhances disulfidptosis in preclinical HCC models. These results improve our understanding of the regulation of disulfidptosis and provide evidence that autophagy acts as a principal suppressor of disulfidptosis, suggesting that pharmacological targeting of the homeostasis between ER stress and autophagy may represent a promising therapeutic approach for the treatment of HCC.

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