Cornuside Mitigates Acute Lung Injury Through Suppression of NLRP3 Inflammasome-Mediated Pyroptosis and Activation of the Keap1-Nrf2 Antioxidant Response

Tong Luo^1,2*Ai Liya³Feng Wang²Wei Yan³Saiyin Chaoketu^3*

• ¹Beijing University of Chinese Medicine, Beijing, China
• ²Wuhan Business University, Wuhan, China
• ³Inner Mongolia International Mongolian Hospital, Hohhot, China

Acute lung injury (ALI) has garnered significant attention in intensive medicine care due to its high mortality rate. Inhibition of NLRP3 inflammasome activation has shown therapeutic potential in various inflammatory diseases, including ALI. Cornus officinalis (Sieb. et Zucc.) is a key herb in traditional Chinese medicine, and among its bioactive components, cornuside (CNS)-a cyclic ether terpene-has attracted growing interest for its bone-protective, neuroprotective, anti-inflammatory, and anti-diabetic properties. In this study, we investigated the therapeutic potential of CNS against ALI and explored its underlying mechanisms. CNS treatment significantly reduced lung inflammation and edema in ALI mice and improved horizontal locomotor activity. RNA sequencing revealed that CNS downregulated inflammatory and oxidative stress-related pathways, suggesting a role in mitigating inflammation. Furthermore, CNS pre-treatment effectively inhibited NLRP3 inflammasome activation, as evidenced by reduced levels of cleaved caspase-1, mature IL-1β release, and subsequent GSDMD-mediated pyroptosis both in vivo and in vitro. CNS also activated the Keap1– Nrf2 pathway, which regulates antioxidant enzymes to reduce oxidative stress. Treatment decreased levels of MPO, MDA, and Keap1 while increasing GSH-PX, Nrf2, GPX4, and NQO1 expression and enhancing Nrf2 nuclear translocation. In conclusion, CNS attenuates NLRP3 inflammasome activation and pyroptosis, and modulates the Keap1-Nrf2 signalling pathway during LPS-induced ALI. These findings highlight CNS as a promising therapeutic candidate for the treatment of ALI.