Apelin-13 activates TFEB-mediated autophagy via AMPK to attenuate senescence and pyroptosis in nucleus pulposus cells during intervertebral disc degeneration.

Abstract

Intervertebral disc degeneration (IDD) is an aging-associated disorder driven by chronic inflammation. Impaired autophagy is a hallmark of disc aging, but its upstream regulation remains unclear. Here, we identify Apelin-13 (APL13) as an endogenous peptide that restores autophagic competence in degenerative nucleus pulposus (NP) cells. APL13 alleviated IL-1β-induced senescence and pyroptosis. It also restored autophagic flux by promoting TFEB activation and nuclear translocation. Mechanistically, APL13 activated AMPK signaling pathways. It enhanced TFEB-dependent lysosomal and autophagy programs through both the AMPK-mTOR axis and the AMPK-FOXO3a-SKP2-CARM1 axis. In a lumbar spine instability mouse model, APL13 preserved disc structure, maintained ECM integrity, and reduced senescence-pyroptosis signaling in vivo. These findings position APL13 as a regulator of disc inflammaging. And the AMPK-TFEB axis emerges as a key pathway linking autophagy restoration to NP cell during IDD progression.