Marine-Derived Quinolinone CHNQD-00603 Triggers Autophagy via Suppressing the AKT/ERK/mTOR Pathway to Reverse Senescence and Restore Osteogenic Potential in Bone Marrow Mesenchymal Stem Cells.

INTRODUCTION

Cellular senescence of Bone Marrow Mesenchymal Stem Cells (BMSCs) acts as a primary driver of age-related bone loss. This study aimed to investigate the anti-senescence potential of CHNQD-00603, a marine-derived quinolone derivative, and its underlying molecular mechanism in BMSCs.

METHODS

BMSCs isolated from Sprague-Dawley rats were induced to senesce using D-galactose and treated with CHNQD-00603. The study employed SA-β-gal staining, qRT-PCR, Western blotting, and transmission electron microscopy to evaluate cellular senescence, osteogenic differentiation, and autophagic flux. Key signaling pathways were analyzed through the phosphorylation status of AKT, ERK, and mTOR.

RESULTS

CHNQD-00603 significantly reduced the proportion of SA-β-gal-positive cells (P < 0.001) and downregulated senescence markers p16 (P< 0.05) and p21 (P < 0.001). Concurrently, it restored osteogenic potential, increasing the expression of RUNX2 (P < 0.001), ALP (P < 0.01), OPN (P < 0.001), and OCN (P < 0.001). Mechanistically, CHNQD-00603 activated autophagy by inhibiting the AKT/ERK/mTOR pathway, as manifested by an increased LC3-II/LC3-I ratio, decreased p62 levels, and autophagosome accumulation.

DISCUSSION: These findings highlight CHNQD-00603 as a dual regulator that suppresses senescence while promoting osteogenesis. Although the study is limited by a lack of in vivo validation, it effectively positions this marine-derived compound as a specific modulator of autophagy-dependent signaling.

CONCLUSION

CHNQD-00603 mitigates BMSC senescence and restores osteogenic capacity by activating AKT/ERK/mTOR-mediated autophagy, making it a promising therapeutic candidate for the treatment of age-related skeletal disorders.