Metformin as a Metabolic Reprogramming Interface in Host-Pathogen and Bone Microenvironment Crosstalk: A Dual-Target...

Metabolic dysregulation is increasingly recognized as a central feature linking chronic infection, immune dysfunction, and skeletal deterioration; however, these processes are most often investigated in isolation, limiting the development of integrative mechanistic frameworks. In this review, we propose the Metabolic Reprogramming Interface Model (MRIM) as a systems-level, hypothesis-generating construct that conceptualizes metabolism as a shared regulatory axis bridging host-pathogen interactions and bone microenvironment remodeling. Importantly, MRIM is not presented as a unified or experimentally validated disease model, but rather as a structured framework designed to organize and critically evaluate emerging multidisciplinary evidence. At the molecular level, metformin, a widely used metabolic modulator, has been shown to influence mitochondrial bioenergetics, AMP-activated protein kinase (AMPK) signaling, redox balance, and autophagic pathways, all of which are independently implicated in microbial persistence, immune cell function, and skeletal homeostasis. Within MRIM, these observations are integrated to hypothesize that metabolic perturbation may coordinately influence infection dynamics, inflammatory responses, and bone turnover. Nevertheless, most of the supporting evidence remains indirect, arising from in vitro studies, animal models, and observational clinical datasets, thereby limiting causal inference. To address this, the framework explicitly distinguishes between experimentally validated mechanisms, context-dependent biological interactions, and higher-order theoretical integrations. While preliminary findings suggest that metformin may modulate microbial fitness, attenuate excessive inflammation, and influence bone remodeling, these effects appear to be highly context-dependent and have not yet been substantiated in adequately powered prospective clinical trials evaluating combined infectious and skeletal outcomes. This review therefore provides a critical synthesis of current knowledge, highlights key mechanistic and translational uncertainties, and outlines testable hypotheses for future investigation, positioning MRIM as a conceptual scaffold to guide interdisciplinary research rather than a definitive explanatory model.