Serine protease inhibitor from Trichinella spiralis ameliorates diet-induced obesity and adipose tissue inflammation through TIM-3-dependent macrophage reprogramming

Pro-inflammatory M1 polarization of adipose tissue macrophages (ATMs) drives adipose inflammation and obesity, suggesting that reprogramming ATM polarization holds therapeutic promise. Parasitic helminths have co-evolved with hosts to induce immune tolerance via M2 polarization, making helminth-derived M2-inducing molecules a potential therapeutic strategy against metabolic disorders. This study aimed to develop a defined serine protease inhibitor derived from Trichinella spiralis (Ts-SPI) as a novel immunomodulatory candidate against diet-induced metabolic disorders. In a high-fat diet (HFD)-induced obese mouse model, recombinant Ts-SPI (rTs-SPI) attenuated obesity and adipose tissue inflammation, and this effect was associated with its ability to reprogram macrophage polarization. In vitro studies confirmed that rTs-SPI drives phenotypic changes in both RAW264.7 cells and bone marrow-derived macrophages (BMDMs). Notably, a free fatty acid (FFA)-stimulated inflammatory adipocyte model and adoptive transfer assays demonstrated that rTs-SPI-reprogrammed macrophages mediate the anti-obesity and anti-inflammatory effects. Mechanistically, TIM-3 was identified as a key mediator through in vivo TIM-3 blockade assays. Pharmacological inhibition revealed downstream PI3K/AKT/mTOR signaling. In summary, this study identifies a parasite-derived protein as a potent TIM-3-targeting biologic candidate for treating metabolic inflammation, proposes a novel “helminth-inspired checkpoint modulation” strategy, and provides new insight into parasite-host immune crosstalk.