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

Oct 29, 2025Cellular & molecular biology letters

PPARγ-Axl pathway may reduce spine disc degeneration by activating cell cleanup to prevent iron-dependent cell death

AI simplified

Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

PPARγ overexpression in intervertebral discs alleviated intervertebral disc degeneration in rat models.

Intervertebral disc degeneration (IVDD) is linked to excessive death of nucleus pulposus cells (NPCs) and degradation of the extracellular matrix (ECM).
, an iron-dependent cell death mechanism, is identified as a significant contributor to IVDD.
Treatment with a PPARγ agonist (pioglitazone) and a ferroptosis inhibitor (ferrostatin-1) preserved ECM homeostasis by reducing matrix metalloproteinases and ferroptosis markers.
Knockdown of PPARγ increased ferroptosis and ECM degradation, indicating its protective role against oxidative stress in NPCs.
PPARγ is associated with the regulation of ferroptosis and ECM homeostasis through autophagy.
The PPARγ-Axl axis may play a critical role in mitigating oxidative stress-induced ferroptosis in NPCs.

AI simplified

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). , 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.

Full Text

We can’t show the full text here under this license. Use the link below to read it at the source.

View full text (PDF) ↗View full text (HTML) ↗

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

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief