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. 2025 Apr 8;20(1):20220913.
doi: 10.1515/biol-2022-0913. eCollection 2025.

Stigmasterol alleviates endplate chondrocyte degeneration through inducing mitophagy by enhancing PINK1 mRNA acetylation via the ESR1/NAT10 axis

Hao Li  1   2 , Xiaofeng Chen  2 , Baoci Huang  3 , Junjie He  1 , Junxian Xie  2 , Weijun Guo  2 , Jinjun Liang  2 , Jiajian Ruan  2 , Jincheng Liu  2 , Zhen Xiang  2 , Lixin Zhu  1
Affiliations

Stigmasterol alleviates endplate chondrocyte degeneration through inducing mitophagy by enhancing PINK1 mRNA acetylation via the ESR1/NAT10 axis

Hao Li et al. Open Life Sci. .

Abstract

Intervertebral disc degeneration (IVDD) is a core factor in spinal degeneration. To date, there is no effective treatment for IVDD. It is urgent to identify the pathogenesis of IVDD to develop effective strategies for IVDD treatment. Alleviating endplate chondrocyte degeneration is a promising strategy for IVDD treatment, while mitophagy prevents degeneration of endplate chondrocytes. Stigmasterol (STM) protects neurons from injuries by triggering mitophagy, yet the effect of STM on the mitophagy of endplate chondrocytes in IVDD has not been reported. In this study, endplate chondrocyte degeneration was induced by interleukin-1β, and the ribonucleic acid (RNA) acetylation level was identified by acetylated RNA immunoprecipitation. Herein, results indicated that STM alleviated endplate chondrocyte degeneration. Besides, STM induced PTEN-induced kinase 1 (PINK1)-mediated mitophagy in degenerated endplate chondrocytes. Moreover, N-acetyltransferase 10 (NAT10) increased PINK1 expression by improving PINK1 mRNA acetylation in endplate chondrocytes. In addition, STM regulated NAT10 expression by estrogen receptor 1 (ESR1) in degenerated endplate chondrocytes. In summary, the present study revealed that STM attenuated endplate chondrocyte degeneration through inducing mitophagy by enhancing PINK1 mRNA acetylation via the ESR1/NAT10 axis. These findings would provide novel strategies for the treatment of IVDD.

Keywords: RNA acetylation; endplate chondrocyte degeneration; intervertebral disc degeneration; mitophagy; stigmasterol.

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Conflict of interest statement

Conflict of interest: Authors state no conflict of interest.

Figures

Figure 1
Figure 1
STM alleviates the degeneration of endplate chondrocytes. (a) Protein levels of MMP3 and MMP13 in mouse endplate chondrocytes treated with or without IL-1β or IL-1β plus STM. (b) mRNA levels of MMP3 and MMP13 in mouse endplate chondrocytes treated with or without IL-1β or IL-1β plus STM. STM: stigmasterol. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
Figure 2
Figure 2
STM triggers PINK1-mediated mitophagy in degenerated endplate chondrocytes. (a) A network constructed based on the HERB database to analyze the correlation between STM and genes involved in mitophagy. (b) The mRNA level of PINK1 in mouse endplate chondrocytes treated with or without IL-1β or IL-1β plus STM. (c) The co-location of MTR and LC3II in mouse endplate chondrocytes treated with or without IL-1β or IL-1β plus STM. (d) Protein levels of LC3II and Parkin in mouse endplate chondrocytes treated with or without IL-1β or IL-1β plus STM. STM: stigmasterol; MTR: MitoTracker Red. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.
Figure 3
Figure 3
NAT10 elevates PINK1 expression by regulating RNA acetylation in endplate chondrocytes. (a) The potential ac4C site in PINK1 mRNA. (b) The mRNA level of PINK1 in mouse endplate chondrocytes treated with or without NAT10 siRNA. (c) The ac4C level of PINK1 mRNA detected by acRIP in mouse endplate chondrocytes treated with or without NAT10 siRNA. NC: negative control. *P < 0.05, ****P < 0.0001.
Figure 4
Figure 4
ESR1 promotes NAT10 gene transcription in endplate chondrocytes. (a) The potential ESR1 binding sites in NAT10 gene promoter. (b) The mRNA level of NAT10 in mouse endplate chondrocytes treated with or without ESR1 siRNA. (c) The protein level of NAT10 in mouse endplate chondrocytes treated with or without ESR1 siRNA. (d) The transcription activity of WT or MUT NAT10 gene promoter was analyzed by relative luciferase reporter activity assay in mouse endplate chondrocytes treated with or without ESR1 siRNA. NC: negative control. **P < 0.01, ****P < 0.0001.
Figure 5
Figure 5
STM increases NAT10 expression by ESR1 in degenerated endplate chondrocytes. (a) The mRNA level of ESR1 in mouse endplate chondrocytes treated with or without IL-1β or IL-1β plus STM. (b) ESR1 protein level in mouse endplate chondrocytes treated with or without IL-1β or IL-1β plus STM. STM: stigmasterol. *P < 0.05, **P < 0.01.
Figure 6
Figure 6
Schematic diagram of regulatory mechanisms for this study. This study revealed that STM alleviated endplate chondrocyte degeneration. Besides, STM induced PINK1-mediated mitophagy in degenerated endplate chondrocytes. Moreover, NAT10 increased PINK1 expression by improving PINK1 mRNA acetylation in endplate chondrocytes. In addition, STM regulated NAT10 expression by ESR1 in degenerated endplate chondrocytes.
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