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Across cancer subtypes, pancreatic cancer has one of the highest cachexia incidence rates at \u223c80%. Given the advanced age of most pancreatic cancer patients, we sought to query cancer-associated muscle wasting using an age-matched murine model. We found that histamine and histamine decarboxylase (HDC) activity were specifically elevated in the muscles of aged tumor-bearing mice. We further found that (1) wasting stimuli induced histamine production and enhanced HDC activity; (2) exogenous histamine was sufficient to induce atrophy-associated gene expression; (3) inhibition of HDC activity by \u03b1-fluoromethylhistidine (FMH) protected against atrophy; (4) treatment of tumor-bearing mice with FMH rescued muscle wasting; and (5) a calcineurin inhibitor was able to rescue histamine-associated increases in calcium\/atrogene signaling. In summary, we present a novel metabolic pathway that has significant implications for the treatment of cachectic cancer patients.<\/jats:p>","DOI":"10.1084\/jem.20242239","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T02:20:46Z","timestamp":1749176446000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Histidine decarboxylase inhibition attenuates cancer-associated muscle wasting"],"prefix":"10.1084","volume":"222","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7479-1149","authenticated-orcid":true,"given":"Aneesha","family":"Dasgupta","sequence":"first","affiliation":[{"name":"Cell Biology and Physiology, Indiana University School of Medicine 1 Department of Anatomy, , Indianapolis, IN,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/00g1d7b60","id-type":"ROR","asserted-by":"publisher"}],"name":"Indiana University Simon Comprehensive Cancer Center 2 , Indianapolis, 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