Highly Potent and Selective TRPM2 Inhibitors: Therapeutic Effects and Mechanisms in Acute Lung Injury.

Acute lung injury (ALI) remains a clinical challenge due to scarce therapeutic targets and insufficient drug specificity, with lipopolysaccharide (LPS) as a key inducer of infection-related ALI. The transient receptor potential melastatin 2 (TRPM2) channel mediates pulmonary inflammation, oxidative stress and apoptosis, but its role in LPS-induced ALI and the lack of selective inhibitors hinder clinical translation. This study evaluated three classes of self-developed TRPM2 inhibitors. In vitro screening identified N-(p-amylcinnamoyl) anthranilic acid (ACA) analogs (compounds 5, 8, 9) that exert significant protective effects against LPS-induced cell damage, along with prominent anti-apoptotic, anti-inflammatory and antioxidant activities, with no obvious cytotoxicity. In vivo, compounds 8 and 9 showed favorable safety profiles, significantly improved lung pathology and function, mitigated hepatorenal impairment and increased the 7-day survival rate of LPS-induced ALI mice. Mechanistically, they inhibited TRPM2 activation at both transcriptional and protein levels, blocking the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome and cysteine aspartyl protease-3 (caspase-3) pathway. Collectively, selective TRPM2 inhibitors, especially compound 8, are promising candidates, providing experimental evidence for TRPM2-targeted ALI therapy.