MOTS‑c, a tiny peptide made by mitochondria, helped protect disc‑stem cells from oxidative damage in lab dishes and in rats, mainly by turning on the AMPK‑SIRT1 pathway. The researchers also built a gel that slowly releases MOTS‑c, which improved cell survival and disc health in animals, but the work is still early‑stage and not yet ready for human use.

Intervertebral disc degeneration (IDD) is characterized by oxidative-stress driven progressive apoptosis and senescence of nucleus pulposus mesenchymal stem cells (NP-MSCs). MOTS-c, a 16-amino acid peptide encoded by the mitochondrial 12S rRNA open reading frame, has emerged as a key regulator of cellular metabolism, oxidative stress, and senescence. This study investigated the therapeutic potential of MOTS-c in countering tert-butyl hydroperoxide (TBHP)-induced oxidative damage in NP-MSCs, and we developed a novel biomaterial strategy for IDD treatment.Key findings include. MOTS-c significantly attenuated TBHP-induced NP-MSC apoptosis (Annexin V+/PI + cells reduced by 48 %, p < 0.001), senescence (SA-β-gal + cells decreased by 52 %, p < 0.005), and ROS overproduction (35 % reduction, p < 0.0001) via activation of the AMPK/SIRT1 pathway. Pharmacological inhibition of SIRT1 abolished these protective effects, confirming pathway specificity. A sustained-release MOTS-c delivery system (RAD/RMOTS-c) was engineered by conjugating MOTS-c to the self-assembling RADA16-I peptide. The hydrogel exhibited a β-sheet-rich nanofibrous structure (fiber diameter: 362.6 nm), shear-thinning rheology (viscosity: 131-217 Pa s), and sustained peptide release over 7 days. RAD/RMOTS-c enhanced NP-MSC viability (1.8-fold vs. control, p < 0.005) and extracellular matrix (ECM) synthesis, elevating collagen II/aggrecan expression (2.3-fold, p < 0.05) while suppressing collagen I (63 % reduction, p < 0.001).In Vivo Therapeutic Validation: In a rat IDD model, RAD/RMOTS-c injection preserved disc height (DHI%: 82.4 vs. 58.7 in IDD group, p < 0.001), restored T2-weighted MRI signals (1.5-fold increase, p < 0.001), and reduced histological degeneration scores by 44 % compared to untreated controls (p < 0.001). This work (1) demonstrates the association between MOTS-c's anti-degenerative effects and AMPK/SIRT1 signaling in NP-MSCs and (2) pioneers a peptide-hydrogel hybrid system that synergistically combines mitochondrial protection with structural support for disc regeneration. The findings can advance IDD therapy toward biology-driven, minimally invasive solutions, aligning with the paradigm of functional biomaterials for degenerative diseases.