Gut Microbiota-Derived Indole-3-Propionic Acid Alleviates Diabetic Osteoporosis Through Nrf2-Mediated Ferroptosis...

Diabetic osteoporosis combines impaired bone formation with disproportionate skeletal fragility, yet the microbial metabolites linking diabetes-associated dysbiosis to bone dysfunction remain unclear. This study implicates indole-3-propionic acid (IPA), a gut microbiota-derived tryptophan metabolite, in the maintenance of skeletal homeostasis under diabetic conditions. Circulating IPA was lower in diabetic mice and in a small exploratory cohort of patients with diabetic osteoporosis. IPA concentrations were positively associated with bone mass. Metagenomic profiling linked lower IPA to impaired microbial tryptophan metabolism and reduced Clostridium abundance. In diabetic mice, IPA supplementation improved trabecular microarchitecture and bone formation. In bone marrow mesenchymal stem cells subjected to high glucose and palmitate, IPA also restored GPX4 and SLC7A11 expression and was associated with recovery of Nrf2-mediated antioxidant signaling. Pharmacological inhibition of Nrf2 substantially attenuated these anti-ferroptosis and pro-osteogenic effects. Together, these findings support a gut microbiota-IPA-Nrf2-ferroptosis pathway linking altered microbial tryptophan metabolism to impaired osteogenesis. They provide a rationale for evaluating IPA as a potential therapeutic strategy for diabetic osteoporosis.