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Transmembrane Protein 175 (TMEM175) is a key regulator of lysosomal pH, and its deficiency is reported to cause lysosomal over\u2010acidification and impaired cathepsin D (CTSD) activity. However, the role of TMEM175 in sepsis remains uncertain. We hypothesize that TMEM175 deficiency exacerbates sepsis by impairing CTSD activity. TMEM175 mRNA expression levels were measured in peripheral blood mononuclear cells (PBMCs) from septic patients and healthy controls (HCs). Using a cecal ligation and puncture (CLP) mouse model, we evaluated the effects of the TMEM175 inhibitor 2\u2010phenylcyclopentylamine (2\u2010PPA) on mortality and bacterial load in target organs. In vitro, TMEM175\u2010knockdown in macrophages was performed to assess its impact on bacterial clearance, phagocytosis, lysosomal acidification, and cathepsin maturation. Results showed that TMEM175 expression was significantly downregulated in PBMCs from septic patients. Pharmacological inhibition of TMEM175 in CLP mice exacerbated bacterial burden and increased mortality. Mechanistically, TMEM175 deficiency impaired macrophage\u2010mediated bacterial clearance, despite having no effect on the initial phagocytic uptake. This dysfunction was attributed to TMEM175, which directly regulates cathepsin transcription. Additionally, TMEM175 deficiency suppressed PI3K\u2013Akt signaling, reducing inflammatory cytokine production.<\/jats:p>","DOI":"10.1155\/jimr\/2046607","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T12:02:52Z","timestamp":1789732972000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Macrophage TMEM175\u2010Mediated Transcriptional Regulation of Cathepsins Drives Bacterial Killing in 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