{ "abstract": "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. Author summary: Pro-inflammatory M1 polarization of adipose tissue macrophages (ATMs) serves as a key driver of metabolic inflammation. Repolarizing ATMs toward an anti-inflammatory M2 state represents a promising therapeutic strategy. Parasitic helminths naturally induce M2 responses to evade host immunity, suggesting they could serve as a natural source of therapeutic molecules. Here we demonstrate that a defined serine protease inhibitor derived from Trichinella spiralis (Ts-SPI) effectively counteracts obesity in high-fat diet-fed mice. rTs-SPI treatment attenuates adipose inflammation and reprograms ATMs from M1 to M2 phenotype. rTs-SPI-triggered immunomodulation was confirmed in RAW264.7 cells and bone marrow-derived macrophages. The functional role of rTs-SPI-reprogrammed macrophages was validated using a free fatty acid-stimulated adipocyte model and adoptive transfer assays. Mechanistically, in vivo immune checkpoint TIM-3 blockade identified TIM-3 as a key mediator, with downstream PI3K/AKT/mTOR signaling involved. This study identifies a parasite-derived biologic candidate, supports a novel “helminth-inspired checkpoint modulation” strategy for metabolic inflammation, and provides new insight into parasite-host immune crosstalk.", "abstract_shown": true, "affiliations": [ "Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China", "School of Basic Medical Sciences, Shanxi Medical University, Jinzhong, China", "Shanxi Key Laboratory of Metabolic-Immune Homeostasis and Drug Innovation, Shanxi Medical University, Jinzhong, China", "Key Laboratory of Cellular Physiology (Shanxi Medical University), Ministry of Education, and Shanxi Key Laboratory of Cellular Physiology, Taiyuan, China", "Department of Infectious Diseases, First Hospital of Shanxi Medical University, Taiyuan, Shanxi, China" ], "article_type": "Research Article", "arxiv": null, "author_total": 9, "authors": [ { "affs": [ 0 ], "name": "Mingwei Tong" }, { "affs": [ 1 ], "name": "Ge Liu" }, { "affs": [ 2 ], "name": "Guidong Ren" }, { "affs": [ 3 ], "name": "Wangxuan Zhang" }, { "affs": [ 4 ], "name": "Yuyu Qiao" }, { "name": "Xiaodan Yang" }, { "name": "Weiping Fan" }, { "name": "Hui Yang" }, { "name": "Yong Yang" } ], "bibtex": "https://research.draconitic.com/paper/0w554g5m44qne.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014606", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014606", "id": "0w554g5m44qne", "issns": [ "1553-7374" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014606", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2713|Adipokines, Inflammation, and Metabolic Diseases" ], [ "plos", "/Biology and life sciences/Anatomy/Biological tissue/Connective tissue/Adipose tissue" ], [ "plos", "/Biology and life sciences/Anatomy/Biological tissue/Connective tissue/Adipose tissue/Adipocytes" ], [ "plos", "/Biology and life sciences/Anatomy/Biological tissue/Connective tissue/Connective tissue cells/Adipocytes" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Blood cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Connective tissue cells/Adipocytes" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Immunology/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Biology and life sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Biology and life sciences/Physiology/Physiological parameters/Body weight" ], [ "plos", "/Biology and life sciences/Physiology/Physiological parameters/Body weight/Obesity" ], [ "plos", "/Medicine and health sciences/Anatomy/Biological tissue/Connective tissue/Adipose tissue" ], [ "plos", "/Medicine and health sciences/Anatomy/Biological tissue/Connective tissue/Adipose tissue/Adipocytes" ], [ "plos", "/Medicine and health sciences/Anatomy/Biological tissue/Connective tissue/Connective tissue cells/Adipocytes" ], [ "plos", "/Medicine and health sciences/Clinical medicine/Signs and symptoms/Inflammation" ], [ "plos", "/Medicine and health sciences/Immunology/Immune cells/White blood cells/Macrophages" ], [ "plos", "/Medicine and health sciences/Immunology/Immune response/Inflammation" ], [ "plos", "/Physical sciences/Mathematics/Statistics/Statistical methods/Analysis of variance" ], [ "plos", "/Research and analysis methods/Mathematical and statistical techniques/Statistical methods/Analysis of variance" ], [ "plos", "/Research and analysis methods/Spectrum analysis techniques/Spectrophotometry/Cytophotometry/Flow cytometry" ] ], "openalex": "W7214308457", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014606&type=printable", "pmcid": null, "pmid": null, "published": "2026-09-25", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/0w554g5m44qne.ris", "sources": [ { "first_seen": "2026-10-30T12:17:43Z", "native_id": "10.1371/journal.ppat.1014606", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014606" } ], "subjects": [ { "field": "biology", "origin": "plos:immunology", "subfield": "immunology" }, { "field": "medicine", "origin": "plos:anatomy", "subfield": "physiology" } ], "title": "Serine protease inhibitor from Trichinella spiralis ameliorates diet-induced obesity and adipose tissue inflammation through TIM-3-dependent macrophage reprogramming", "title_text": "Serine protease inhibitor from Trichinella spiralis ameliorates diet-induced obesity and adipose tissue inflammation through TIM-3-dependent macrophage reprogramming", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:43Z", "url": "https://research.draconitic.com/paper/0w554g5m44qne", "venue": "PLOS Pathogens", "versions": [] }