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Using a fluorescence-dilution reporter system in\n                    <jats:italic>Salmonella<\/jats:italic>\n                    Typhimurium (\n                    <jats:italic>Salmonella<\/jats:italic>\n                    )-infected macrophages, we found that Protein Phosphatase 6 (Pp6) was downregulated in macrophages harboring growing bacteria. Conditional knockout of\n                    <jats:italic>Pp6<\/jats:italic>\n                    elevated host susceptibility to\n                    <jats:italic>Salmonella<\/jats:italic>\n                    -mediated lethality due to compromised antimicrobial defenses. MicroRNA-31 (miR-31) was identified as a negative regulator of Pp6, and its conditional ablation enhanced bacterial clearance. Yeast two-hybrid screening identified 6-phosphofructo-2-kinase\/fructose-2,6-biphosphatase 1 (Pfkfb1), a metabolic regulator, as a substrate of Pp6.\n                    <jats:italic>Pp6<\/jats:italic>\n                    deficiency resulted in significantly elevated expression of Pfkfb1, which was highly expressed in macrophages containing replicating\n                    <jats:italic>Salmonella<\/jats:italic>\n                    .\n                    <jats:italic>Pfkfb1<\/jats:italic>\n                    deletion restricted bacterial proliferation by promoting nitric oxide (NO) production while concurrently suppressing arginase-1 (Arg-1) expression and impairing arginine metabolism in macrophages. Collectively, these results establish the Pp6-Pfkfb1 axis as a key regulator of host metabolic adaptation and intracellular bacterial survival, offering potential therapeutic targets against multidrug-resistant pathogens.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013304","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T18:52:08Z","timestamp":1767207128000},"page":"e1013304","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pp6-Pfkfb1 axis modulates intracellular bacterial proliferation by orchestrating host-pathogen metabolic 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