Protective effects of diosgenin against non-alcoholic fatty liver disease through inhibiting the STING-dependent inflammatory pathway

Growing evidence suggests that the stimulator of interferon genes (STING)-dependent inflammatory pathway is crucial in the progression of non-alcoholic fatty liver disease (NAFLD). Diosgenin (DG), a natural steroidal saponin, has demonstrated multi-pharmacological potential, such as anti-inflammatory and lipid-lowering capacities. Our previous study confirmed the protective role of DG in rat models of NAFLD. Our present study sought to further explore the protective effects of DG in NAFLD and to determine whether its mechanism involves the STING-dependent inflammatory pathway. In this research, we developed experimental models for both high-fat diet (HFD)-induced NAFLD in rats and steatosis induced by free fatty acids (FFAs) in HepG2 cells. The results revealed that DG treatment significantly reduced body weight, liver index, serum lipid levels, hepatic lipid accumulation, and liver injury in HFD-fed rats. Additionally, DG markedly alleviated mitochondrial dysfunction and suppressed the protein expression of the STING-dependent inflammatory pathway in both in vivo and in vitro NAFLD models. In contrast, administration of cGAMP, a STING agonist, upregulated the STING-dependent inflammatory pathway and exacerbated lipid accumulation and mitochondrial dysfunction in FFAs-induced HepG2 cells. In conclusion, our findings suggested that DG protects against NAFLD by mitigating lipid accumulation and mitochondrial dysfunction, with its mechanism related to the inhibition of the STING-dependent inflammatory pathway.