Curcumin Acts Synergistically with Metformin to Inhibit Autophagy and Promote Pyroptosis in Hepatic Stellate Cells

Background: Hepatic stellate cells play a critical role in liver fibrosis progression through activation and proliferation. Autophagy and pyroptosis have both been reported to play key roles in the activation of HSCs. Objectives: This study aimed to observe the effects of cooperation between curcumin and metformin regarding the regulation of autophagy and pyroptosis in HSCs. Methods: HSCs (line LX-2) and rat T-6 cells were treated with either curcumin or curcumin and metformin combined. The vitality and proliferation of HSCs were then measured, as were the expressions of microtubule-associated light chain 3 (LC3) and ubiquitin-binding protein 62 (P62) to investigate autophagy. The autophagosomes in the HSC cells were quantified using transmission electron microscopy. The pyroptosis-related proteins gasdermin D (GSDMD) and caspase-1 were also measured, as were the expression levels of the inflammatory cytokines lactate dehydrogenase (LDH) and interleukin-1β (IL-1β). Results: When combined with metformin, curcumin significantly reduced the activities of the LX-2 and T-6 cells and significantly induced pyroptosis, as observed by flow cytometry. Furthermore, the expressions of GSDMD and caspase-1 were higher in the curcumin+metformin treatment group than in the curcumin group, and more LDH and 1L-1β were released. Conclusion: When combined with metformin, curcumin can inhibit autophagy and proliferation activity in the HSCs, promote pyroptosis, and play a role in delaying the process of liver fibrosis.