{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:49:42Z","timestamp":1785761382131,"version":"3.56.0"},"reference-count":42,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jiangsu Provincial Science and Technology Plan Special Fund","award":["BE2023841"],"award-info":[{"award-number":["BE2023841"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Background\/Objectives: Human islet amyloid polypeptide (IAPP) aggregation plays a critical role in the pathogenesis of type 2 diabetes mellitus (T2DM). Although metabolic alterations are a hallmark of T2DM, the functional roles of differential metabolites in regulating disease-associated molecular processes remain largely unexplored. This study aimed to establish a metabolomics-guided strategy for identifying endogenous metabolites with anti-amyloid activity and to investigate their underlying chemical interactions with IAPP. Methods: Untargeted metabolomic profiling of clinical samples from T2DM patients, obesity patients and healthy controls was performed to identify differential metabolites. Candidate metabolites were subsequently screened for their ability to modulate IAPP aggregation. Transmission electron microscopy (TEM), thioflavin T (ThT) fluorescence assays, and cell viability measurements were employed to evaluate their effects on fibril formation and cytotoxicity. Mass spectrometry was further used to characterize metabolite\u2013IAPP interactions. Results: Metabolomic analysis identified 3-hydroxypyruvic acid (also known as \u03b2-hydroxypyruvic acid, hereafter referred to as HPA) as a significantly altered endogenous metabolite associated with T2DM and a candidate regulator of IAPP aggregation. Functional assays demonstrated that HPA effectively inhibited amyloid fibril formation, as evidenced by the absence of typical fibrillar structures and a prolonged lag phase during aggregation. HPA also significantly alleviated IAPP-induced cytotoxicity. Mass spectrometric analysis revealed the formation of HPA\u2013IAPP oligomer complexes (n &lt; 4), suggesting that HPA directly interacts with early oligomeric intermediates and interferes with their progression toward mature fibrils. Conclusions: This work demonstrates that untargeted metabolomics of clinical samples can serve as an effective strategy for discovering bioactive endogenous metabolites involved in disease-related molecular processes. The identification of HPA as a potential endogenous inhibitor of IAPP aggregation provides new chemical insight into the relationship between metabolic dysregulation and amyloidogenesis and highlights endogenous metabolites as a valuable source of potential therapeutic lead compounds.<\/jats:p>","DOI":"10.3390\/metabo16080549","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:50:21Z","timestamp":1785757821000},"page":"549","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Metabolomics-Based Strategy for Identifying Endogenous Inhibitors of IAPP Aggregation"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6208-1518","authenticated-orcid":false,"given":"Dandan","family":"Xia","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, China"},{"name":"The State Key Lab of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China"},{"name":"Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Tongjiaxiang #24, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liubao","family":"Gu","sequence":"additional","affiliation":[{"name":"Division of Clinical Epidemiology, Geriatric Hospital of Nanjing Medical University, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Tongjiaxiang #24, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaojiao","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Tongjiaxiang #24, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1886-2728","authenticated-orcid":false,"given":"Xiaowei","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Tongjiaxiang #24, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dechen","family":"Jiang","sequence":"additional","affiliation":[{"name":"The State Key Lab of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuling","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Analysis, School of Pharmacy, China Pharmaceutical University, Tongjiaxiang #24, Nanjing 210009, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Miraee-Nedjad, S., Sims, P.F.G., Schwartz, J.M., and Doig, A.J. 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