Cisplatin Promotes Hepatotoxicity by cGAS‐STING Mediated Innate Immune Response

Although platinum-based chemotherapy represented by cisplatin has been widely approved for the management of diverse cancer types, its hepatotoxicity and other adverse effects impact patient prognosis, while currently, there are few effective strategies for prevention or treatment. RNA sequencing analysis indicated that the type I interferon (IFN-I) pathway was significantly upregulated in cisplatin-induced liver injury (CILI) mouse model. The cGAS-STING signaling was found to be significantly activated in vitro and CILI model in vivo. Mechanistically, cisplatin-induced DNA damage triggered the release of double-stranded DNA (dsDNA), which subsequently activated the cGAS-STING pathway. The activated pathway promoted the production of IFN-I and induced apoptosis, ultimately contributing to liver injury. Importantly, inhibition of the cGAS-STING pathway, either by enzymatic digestion of dsDNA or by genetic knockout of cGAS, effectively attenuated IFN-I production and liver injury in response to cisplatin. Overall, our results highlight the cGAS-STING-IFN-I axis as a promising therapeutic target for preventing and treating platinum-based drug-induced liver damage.