Organ‐Resolved Host Proteomic and Post‐Translational Modification Landscapes in a Mouse Model of Talaromyces marneffei Infection

The infection of Talaromyces marneffei (T. marneffei, TM ) causes disseminated diseases requiring coordinated multi‐organ host responses. Post‐translational modifications (PTMs) regulate protein functions, but the tissue patterns during T. marneffei infection remain incompletely characterized. In this study, global proteomics and profiling of phosphorylation, ubiquitination, acetylation, and lactylation were performed on mouse liver, lung, and spleen samples after T. marneffei infection. Differential and cross‐organ analyses were performed, and kinase activity was inferred computationally to nominate exploratory candidate interventions. Global proteomics revealed a systemic inflammatory response with extensive activation of innate and adaptive immune pathways and profound metabolic perturbation. These changes were evident across all organs, but different tissues exhibited unique regulatory characteristics. Cross‐omics functional comparison showed limited detected overlap at individual lysine positions and shared pathway associations. Metabolic reprogramming was a common feature across organs, accompanied by extensive PTM change of metabolic state and chromatin regulation. Computational analysis suggested organ‐dependent kinase‐associated phosphorylation signatures. In exploratory in vivo testing, selected candidates, including pitavastatin, reduced fungal burden and improved survival, supporting further evaluation of this candidate‐prioritization strategy. In conclusion, this study systematically characterized the panoramic proteomic and PTM landscape during T. marneffei infection, providing a resource for studying host regulatory responses in fungal infections.