ED-71 ameliorates oxeiptosis-associated signaling in BMSCs under diabetic osteoporosis by alleviating PKM2-associated metabolic dysregulation and mitochondrial dysfunction.

Authors

Rundong Yuan, Yajun Cui, Junyang Sun, Hongrui Liu, Jie Guo, Yuping Qi, Juan Du, Minqi Li

Published in

Cellular signalling. Pages 112946. Oct 13, 2026. Epub Oct 13, 2026.

Abstract

Diabetic osteoporosis (DOP) poses a significant clinical challenge, characterized by elevated fracture risk linked to bone quality deterioration. The pathogenesis involves reactive oxygen species (ROS) accumulation and metabolic dysfunction in bone marrow mesenchymal stem cells (BMSCs). This study investigates the role of oxeiptosis, a novel ROS-triggered, caspase-independent cell death pathway, in DOP and explores the therapeutic potential of Eldecalcitol (ED-71). In a type 2 diabetes mouse model, ED-71 treatment significantly ameliorated bone loss and suppressed the upregulation of oxeiptosis-associated molecular changes in BMSCs. In vitro, high glucose (HG) conditions induced oxeiptosis-associated signaling, mitochondrial dysfunction, a glycolytic shift, and impaired osteogenic differentiation in BMSCs. ED-71 intervention partially counteract these effects. Mechanistic studies predicted a potential molecular interaction between ED-71 and PKM2, a key regulator of glycolysis, which reduced its abundance and reversed metabolic imbalance. These effects were accompanied by improved mitochondrial function and enhanced Nrf2/GPX4-mediated antioxidant defense, ultimately suppressing the KEAP1/PGAM5/AIFM1 oxeiptosis-associated signaling. Pharmacological activation of PKM2 by TEPP-46 partially reversed ED-71's protective effects, supporting a functional involvement of PKM2 in the observed mechanism, although genetic validation is required to establish causality. In conclusion, ED-71 may alleviate mouse DOP by reducing PKM2 expression to correct metabolic reprogramming and mitochondrial dysfunction, thereby suppressing oxeiptosis and restoring HG-treated BMSCs' osteogenic potential, offering a novel mechanistic foundation for its therapeutic application.

PMID:
42869321
Bibliographic data and abstract were imported from PubMed on 14 Oct 2026.

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