Activating the Osteoblastic USP26 Pathway Alleviates Multi‐Organ Fibrosis by Decreasing Insulin Resistance

Osteoblast dysfunction contributes to systemic metabolic disorders by inducing insulin resistance (IR), a key factor in metabolic-related fibrosis. Therefore, the axis of osteoblast dysfunction, IR, and multi-organ fibrosis represents a crucial pathological pathway. This study revealed that the deletion of Ubiquitin Specific Peptidase 26 (USP26) in osteoblasts leads to decreased bone formation along with multi-organ fibrosis associated with IR. Mechanistically, the loss of USP26 decreases histone H3 lysine 18 lactylation (H3K18LA) in the promoter region of KH-Type Splicing Regulatory Protein (KSRP), resulting in decreased expression of KSRP and decreased alternative splicing of follistatin-like protein 1 (FSTL1) mRNA by KSRP. Elevated FSTL1 expression causes IR and high blood glucose levels, which leads to advanced glycation end-product (AGE) accumulation in the blood and multi-organ fibrosis. Activation of the USP26 pathway, specifically in osteoblasts, through extracellular vesicle-based bone-targeting drugs or mechanical loading can effectively prevent multi-organ fibrosis induced by IR. This study uncovered a causal relationship between skeletal degeneration and metabolism-related fibrosis, and highlights osteoblastic USP26 as a promising therapeutic target for addressing multi-organ fibrosis associated with IR.