6-Shogaol attenuates liver fibrosis by driving hepatic stellate cell senescence through the cGAS-STING-NF-κB axis.

BACKGROUND: Liver fibrosis represents a frequent pathological outcome of chronic hepatic insults. As a bioactive constituent of ginger, 6-shogaol has shown hepatoprotective potential. Hepatic stellate cell (HSC) activation is widely regarded as an important driver in the occurrence and advancement of liver fibrosis. However, whether 6-shogaol can regulate HSC activation remains to be dissected. PURPOSE: To assess the anti-fibrotic effects of 6-shogaol and elucidate the molecular mechanisms, we focused on its impact on the fate of HSCs and the subsequent alleviation of liver fibrosis. METHODS: A CCl₄-induced mouse model and LX-2 cells were employed to evaluate the antifibrotic efficacy of 6-shogaol and explore the underlying mechanisms. Unbiased combined transcriptomic and proteomic profiling was performed to identify candidate mechanisms, which were further validated in LX-2 cells, mouse HSC-enriched fractions derived from fibrotic livers, and through in vivo pharmacological and genetic loss-of-function approaches. RESULTS: Treatment with 6-shogaol alleviated hepatic injury, inflammation, and fibrogenesis in mice, while suppressing HSC activation. Mechanistically, integrated transcriptomic and proteomic analyses identified cGAS-STING-NF-κB axis-mediated senescence as a key mechanism underlying the anti-activation effect of 6-shogaol on HSC. Pharmacological blockade of individual nodes within this signaling cascade significantly reversed 6-shogaol-induced senescence and blunted its anti-activation effect in LX-2 cells. Consistently, short-term administration of 6-shogaol in fibrotic mice, followed by isolation of HSC-enriched fractions, further confirmed that 6-shogaol promotes senescence and engages the cGAS-STING-NF-κB axis in vivo. Finally, in vivo pharmacological blockade and STING knockdown markedly blunted the antifibrotic efficacy of 6-shogaol. CONCLUSION: Treatment with 6-shogaol attenuates liver fibrosis by driving HSC senescence through the cGAS-STING-NF-κB axis. These findings further expand the molecular understanding of the antifibrotic mechanisms of 6-shogaol and provide more mechanistic rationale for its therapeutic application.