CNS-penetrant NLRP3 inhibitor TN-783 achieves durable weight loss and reverses hypothalamic inflammation in diet-induced obesity

The NLRP3 inflammasome is a key mediator of innate immunity that integrates inflammatory and metabolic stress signals. Increased chronic activation of this critical pathway has been implicated in obesity, with increased hypothalamic neuroinflammation linked to dysregulation of energy balance. TN-783 is an investigational CNS-penetrant small-molecule NLRP3 inhibitor that potently suppresses inflammasome activation. In diet-induced obese (DIO) mice, TN-783 produced progressive and sustained weight loss. Transcriptomic profiling revealed partial reversal of obesity-associated molecular changes, particularly among genes involved in inflammation and neuronal signaling.