PEP472, an ncRNA-encoded micropeptide, attenuates oxidative stress-induced senescence and preserves TSPC stemness by stabilizing SIRT1.

Tendon stem/progenitor cells (TSPCs) play essential roles in tendon homeostasis and repair, but their regenerative capacity is compromised by oxidative stress-induced senescence and the associated loss of stemness. Here, we identified PEP472, a previously uncharacterized micropeptide encoded by a small open reading frame (smORF) within the long non-coding RNA (lncRNA) MSTRG.44472.1, as a regulator of TSPC function under oxidative stress. The expression of MSTRG.44472.1 decreased in an H₂O₂-induced TSPC senescence model, and the coding potential of its smORF and translation into PEP472 were subsequently validated. Functional analyses demonstrated that PEP472 attenuated H₂O₂-induced senescence, preserved TSPC stemness, and promoted tenogenic differentiation. Mechanistically, PEP472 increased SIRT1 protein abundance by suppressing proteasome-dependent SIRT1 degradation and enhancing SIRT1 stability. Consistent with a role for SIRT1 in mediating the protective effects of PEP472, pharmacological inhibition of SIRT1 with EX-527 markedly attenuated the anti-senescence effects of PEP472. Together, these findings identify a previously unrecognized MSTRG.44472.1-PEP472-SIRT1 regulatory axis in TSPCs and demonstrate that PEP472 attenuates oxidative stress-induced senescence and preserves TSPC stemness through SIRT1 stabilization. This study highlights PEP472 as a promising micropeptide-based biologic candidate for preventing senescence-associated TSPC dysfunction and supporting tendon regenerative repair.