Chemoproteomics of\nMarine Natural Product Naamidine\nJ Unveils CSE1L as a Therapeutic Target in Acute Lung Injury

Acute lung injury is a devastating illness characterized\nby severe\ninflammation mediated by aberrant activation of macrophages, resulting\nin significant morbidity and mortality, highlighting the urgent need\nfor novel pharmacological targets and drug candidates. In this study,\nwe identified a novel target for regulating inflammation in macrophages\nand acute lung injury via chemical proteomics and genetics based on\na marine alkaloid, naamidine J (NJ). The structures of NJ-related\nnaamidine alkaloids were first confirmed or revised by a combination\nof quantum chemical calculations and X-ray diffraction analysis. NJ\nwas found as a potential anti-inflammatory agent by screening our\ncompound library, and CSE1L was identified by chemoproteomics as a\nmain cellular target of NJ to inhibit inflammation in macrophages\nand protect against acute lung injury. Mechanistically, we demonstrated\nthat NJ directly interacted with CSE1L on the sites of His745 and\nPhe903 and then inhibited the nuclear translocation and transcriptional\nactivity of transcription factor SP1, thereby suppressing inflammation\nin macrophages and ameliorating acute lung injury. Taken together,\nthese findings have uncovered a novel pharmacological target for the\ntreatment of acute lung injury and have also provided a potential\ndruggable pocket of CSE1L and a lead compound or an available chemical\ntool from marine sources for investigating CSE1L function and developing\nnovel drug candidates against acute lung injury.