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While bioactive peptides such as melittin show anti-inflammatory potential, their clinical application is limited by cytotoxicity and unclear mechanisms. In this study, we developed HMLT, a melittin-derived peptide with histidine substitutions designed to reduce cytotoxicity. Compared with native melittin, HMLT exhibited significantly lower cytotoxicity in RAW264.7 macrophages while maintaining potent anti-inflammatory activity, as demonstrated by reduced TNF-\u03b1 release and downregulated expression of TNF-\u03b1, IL-6 and IL-1\u03b2. Flow cytometry analysis revealed that HMLT reduced ROS accumulation and protected mitochondrial membrane potential in LPS-stimulated macrophages. Additionally, HMLT decreased nitric oxide release and suppressed inducible nitric oxide synthase expression. Metabolomic analysis showed that HMLT restored metabolic balance by increasing endogenous antioxidants including O-acetylcarnitine and ornithine, while downregulating glycolytic intermediates such as phosphoenolpyruvic acid, 2-phospho-D-glyceric acid and 3-phosphoglyceric acid. In a caerulein and LPS-induced murine SAP model, HMLT administration significantly alleviated pancreatic injury, as evidenced by reduced serum amylase and lipase levels, diminished edema. Further mechanistic studies revealed that HMLT inhibited TNF-\u03b1 secretion and suppressed PKM2-mediated glycolysis in M2-like macrophages. Collectively, these findings demonstrate that HMLT overcomes the toxicity limitations of native melittin and ameliorates SAP through coordinated restoration of oxidative homeostasis and metabolic reprogramming in macrophages, highlighting its promise as a lead compound for SAP treatment.<\/jats:p>","DOI":"10.1007\/s10753-025-02444-9","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T15:54:58Z","timestamp":1769097298000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Melittin-Derived Lead Compound Ameliorates Severe Acute Pancreatitis by Restoring Oxidative Homeostasis and Macrophage Metabolism"],"prefix":"10.1007","volume":"49","author":[{"given":"Xiaolong","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunyun","family":"Mao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinxin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yilin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianfeng","family":"Tu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,1,22]]},"reference":[{"issue":"3","key":"2444_CR1","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1038\/s41575-018-0087-5","volume":"16","author":"MS Petrov","year":"2019","unstructured":"Petrov, M.S., et al. 2019. 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