The contribution of polyol metabolism to pathological bone remodeling remains incompletely understood. Here, we examined its role in osteoclastogenesis and evaluated the skeletal effects of epalrestat, a clinically approved aldose reductase inhibitor. Exploratory single-cell analysis of two human femoral-head specimens suggested greater macrophage-associated polyol-pathway activity in the osteoporosis specimen. In primary bone marrow-derived macrophages, silencing of Akr1b3 and Sord produced opposing effects on osteoclast differentiation. Epalrestat suppressed RANKL-induced osteoclastogenesis and attenuated bone loss in diabetic, ovariectomy-induced, and inflammatory mouse models under early-intervention regimens. Mechanistic analyses showed improved NADPH/NADP⁺ and GSH/GSSG balance, reduced oxidative stress, and attenuated cytosolic and mitochondrial Ca²⁺ signals and Ca²⁺ oscillations. Genetic and osmotic-compensation experiments further supported a model in which intracellular sorbitol contributes to the osmotic regulation of Ca²⁺ oscillations. Additional findings included reduced inflammation in osteolysis and arthritis models, altered macrophage polarization, and partial preservation of bone marrow vascular features. Together, these findings connect glucose metabolism with redox and Ca²⁺ regulation during osteoclast differentiation and provide a rationale for further evaluation of epalrestat in skeletal disease.
Differentiation-based cancer therapy is a potentially low-toxicity approach with demonstrated clinical benefits. However, the therapeutic efficacy of differentiation therapy remains limited in tumor types other than acute promyelocytic leukemia (APL). Our previous studies reported that diptoindonesin G (Dip G), a natural compound, can induce differentiation in both acute myeloid leukemia (AML) cells and basal-like breast cancer cells. In this study, we report a crucial role of GABAA receptor-associated protein-like 1 (GABARAPL1) in driving cancer cell differentiation. By utilizing myeloid cell differentiation models and primary leukemic cells, we demonstrate that upregulation of GABARAPL1 expression was crucial for Dip G-induced differentiation and that Dip G upregulated GABARAPL1 expression by targeting nucleolin (NCL). Also, GABARAPL1 promoted differentiation independent of its autophagic function. Both pharmacological and genetic upregulation of GABARAPL1 expression effectively overcame the differentiation blockade in various tumor models, including AML cells. Mechanistically, GABARAPL1 interacted with splicing factor proline and glutamine rich (SFPQ) and recruited MDM2 to promote the degradation of SFPQ by the proteasome. Upon SFPQ depletion, the transcription of linker histone H1.2 gene was repressed, which in turn rescued the transcription of the differentiation-related pathway. Our study not only highlights the contribution of GABARAPL1 to differentiation but also provides a potential therapeutic strategy aimed at expanding the scope of application of differentiation-based cancer therapy.
