Objective <p>WW and C2 domain-containing 1 (WWC1) is a critical regulator of the Hippo signaling, a key pathway associated with inflammation. The study focuses on the roles of WWC1 in sepsis-induced lung injury (SiLI) and explores the associated regulatory mechanism within this context.</p> Methods <p>Wild-type (wt) and WWC1 knockout (WWC1-ko) mice were subjected to cecal ligation and puncture for sepsis modeling. Levels of WWC1, large tumor suppressor kinase 1 (LATS1), Yes-associated protein 1 (YAP1), stimulator of interferon genes (STING) and the pathway-related proteins, and fibrosis markers in lung tissue were assessed using qPCR, western blot analysis, immunofluorescence, or immunohistochemistry. Histological staining was conducted to assess pathological changes within the lung. BEAS-2B cells were exposed to lipopolysaccharide (LPS) for in vitro modeling.</p> Results <p>WWC1 was downregulated in mice with SiLI, accompanied by decreased phosphorylation of LATS1 and YAP1. WWC1-ko mice exhibited a more severe inflammatory response, mucus production, and fibrosis in lung tissues compared to wt mice, along with increased inflammatory cytokines in bronchoalveolar lavage fluid. The cGAS-STING signaling was activated in WWC1-ko mice as well. Administration of YAP1 or STING antagonists alleviated SiLI in WWC1-ko mice. Interferon regulatory factor 3 (IRF3), an effector of the STING signaling, bound to the WWC1 promoter to repress its transcription. Overexpressing IRF3 in BEAS-2B reduced WWC1 expression and activated YAP1 and the cGAS-STING axis, thus reducing cell viability of LPS-challenged BEAS-2B cells. These observations were negated by the WWC1 overexpression.</p> Conclusion <p>WWC1 plays a protective role in SiLI by reducing nuclear accumulation of YAP1 and suppressing activation of the cGAS-STING signaling. IRF3, a key downstream transcription factor of STING, negatively regulates WWC1, creating a negative feedback loop that exacerbates lung injury.</p>