Transient receptor potential vanilloid 4 exacerbates sepsis-induced acute lung injury by promoting endothelial pyroptosis via the Ca2+/Nrf2/GSDMD signaling pathway.

Sepsis-induced acute lung injury (ALI) is characterized by devastating pulmonary microvascular endothelial dysfunction, yet the specific molecular mechanisms driving this pathological process remain incompletely elucidated. Herein, we identify a critical pro-injury role for the calcium-permeable channel transient receptor potential vanilloid 4 (TRPV4) in exacerbating ALI by orchestrating pulmonary microvascular endothelial pyroptosis. We observed significant upregulation of TRPV4 in lung tissues of cecal ligation and puncture (CLP) induced septic mice at 24 h post surgery. In lipopolysaccharide (LPS) stimulated human pulmonary microvascular endothelial cells (HPMECs), TRPV4 expression was significantly upregulated in a time dependent manner, peaking at 24 h stimulation. Both genetic ablation and pharmacological inhibition of TRPV4 markedly attenuated lung pathological damage, reduced pulmonary edema, and suppressed the secretion of pro-inflammatory pyroptotic cytokines IL-1β and IL-18. Mechanistically, TRPV4 activation triggered intracellular Ca2+ overload, which subsequently inhibited the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), thereby dampening the endogenous antioxidant defense pathway. This signaling disruption promoted gasdermin D (GSDMD) cleavage and the execution of pyroptosis in HPMECs. Further investigations revealed that the pharmacological inhibition of TRPV4 failed to rescue the lung injury phenotype in Nrf2 knockout mice. Collectively, our findings uncover a novel TRPV4/Ca2+/Nrf2/GSDMD signaling axis that drives pulmonary microvascular endothelial pyroptosis in sepsis, providing a promising therapeutic target for mitigating sepsis-induced ALI.