PPARγ-Axl axis ameliorates intervertebral disc degeneration by activating PI3K/AKT-mediated autophagy to suppress ferroptosis.

Peroxisome proliferator-activated receptors (PPARs) play a critical role in the development of intervertebral disc degeneration (IVDD), a major contributor to chronic low back pain (LBP). This condition is characterized by excessive nucleus pulposus cell (NPC) death, which contributes to degradation of the extracellular matrix (ECM). Ferroptosis, an iron-dependent cell death mechanism, has emerged as a key player in IVDD. However, the underlying mechanism and pathogenesis remain incompletely understood. In this study, we aimed to assess the function of PPARγ in IVDD and its modulation of ferroptosis in vivo using rat models of IVDD and in vitro using NPC cultures treated with oxidative stress-inducing agents, such as tert-butyl hydroperoxide (TBHP) and interleukin (IL)-1β. NPC treatment with PPARγ agonist (pioglitazone) and inhibitor of ferroptosis (ferrostatin-1; Fer-1) maintained ECM homeostasis by downregulating matrix metalloproteinases and ferroptosis indicators and upregulating anabolic factors. Conversely, PPARγ knockdown exacerbated ferroptosis and ECM degradation, underscoring its protective effects against oxidative stress-induced ferroptosis in NPCs. PPARγ regulates ferroptosis and ECM homeostasis through autophagy. RNA-sequencing, chromatin immunoprecipitation followed by quantitative polymerase chain reaction (ChIP-qPCR) and co-immunoprecipitation (Co-IP) assays confirmed Axl as a novel binding partner of PPARγ. Furthermore, using a Tet-on dual-inducible system, we demonstrated the involvement of the PPARγ-Axl axis in the alleviation of oxidative stress-induced ferroptosis by autophagy. In vivo, PPARγ overexpression in intervertebral disc (IVD) alleviated IVDD in rat models. In summary, these findings reveal a pivotal role for the PPARγ-Axl axis in mitigating ferroptosis and preserving ECM homeostasis in NPC via autophagy, providing a new therapeutic strategy for IVDD.