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Background <p>Major depressive disorder (MDD) is a leading cause of disability and disease burden worldwide, and increasing attention has been paid to the role of immune dysregulation in MDD pathogenesis. However, the key cellular subsets, hub molecules, and their regulatory mechanisms have not yet been fully elucidated. This study investigated the roles of Sigma-1 receptor (Sigma-1R) and CD36 in myeloid cells, exploring their potential as targets for modulating peripheral inflammation in MDD.</p> Methods <p>We performed a random-effects meta-analysis of five public PBMC transcriptomic cohorts (<i>n</i> = 1388) and analyzed a public PBMC scRNA-seq dataset (MDD, <i>n</i> = 8; HC, <i>n</i> = 8) to characterize cell-type specific expression patterns. CRS mouse experiments and complementary in vitro assays were conducted to examine Sigma-1R regulation of CD36 and the role of the E3 ligase TRIM28, using pharmacological agonism (Hypidone hydrochloride, YL-0919 or SA4503) and antagonism (BD-1047), flow cytometry, cytokine measurements, co-immunoprecipitation, and ubiquitination/proteasome-degradation assays.</p> Results <p>The meta-analysis estimated a small, non-significant pooled difference in CD36 expression in bulk PBMC between the MDD and HC groups (SMD = 0.043, 95% CI −0.144 to 0.231). PBMC scRNA-seq revealed CD36 upregulation mainly in myeloid cells, accompanied by alterations in inflammatory genes and pathways. In CRS mice, myeloid CD36 levels increased in the liver and spleen, whereas Sigma-1R activation reduced CD36, lowered IL-6 and TNF-α, and improved depression-like behaviors. Mechanistically, Sigma-1R interacted with CD36 and promoted K48-linked ubiquitination and proteasome-dependent degradation. TRIM28 was identified as the E3 ubiquitin ligase mediating Sigma-1R–induced CD36 K48-linked ubiquitination, with K469 and K472 serving as critical ubiquitination sites. Knockdown of Sigma-1R in cells attenuated CD36 K48-linked ubiquitination. In vivo, pharmacological blockade with BD-1047 attenuated CD36 downregulation and associated effects, supporting Sigma-1R involvement.</p> Conclusions <p>Our study identifies the myeloid Sigma-1R–CD36 axis in MDD and demonstrates that Sigma-1R promotes CD36 proteasome-dependent degradation via TRIM28-dependent K48-linked ubiquitination. This pathway suggests that CD36 in peripheral myeloid subsets may serve as a measurable immune indicator and supports Sigma-1R–CD36 modulation as a potential therapeutic strategy to mitigate inflammation-associated depressive phenotypes.</p>

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Sigma-1R–CD36 axis in myeloid cells contributes to the alleviation of depression-like behaviors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • Meng Liang,
  • Zhiding Wang,
  • Ge Li,
  • Chunxiao Du,
  • Junrui Chen,
  • Jiawen Lu,
  • Miaonan Sun,
  • Yanmin Lyu,
  • Mengying Huang,
  • Jixiang Sun,
  • Yuxiang Li,
  • Yanhong Liu,
  • Jiangbei Cao,
  • Gencheng Han,
  • Yunfeng Li,
  • Weidong Mi

摘要

Background

Major depressive disorder (MDD) is a leading cause of disability and disease burden worldwide, and increasing attention has been paid to the role of immune dysregulation in MDD pathogenesis. However, the key cellular subsets, hub molecules, and their regulatory mechanisms have not yet been fully elucidated. This study investigated the roles of Sigma-1 receptor (Sigma-1R) and CD36 in myeloid cells, exploring their potential as targets for modulating peripheral inflammation in MDD.

Methods

We performed a random-effects meta-analysis of five public PBMC transcriptomic cohorts (n = 1388) and analyzed a public PBMC scRNA-seq dataset (MDD, n = 8; HC, n = 8) to characterize cell-type specific expression patterns. CRS mouse experiments and complementary in vitro assays were conducted to examine Sigma-1R regulation of CD36 and the role of the E3 ligase TRIM28, using pharmacological agonism (Hypidone hydrochloride, YL-0919 or SA4503) and antagonism (BD-1047), flow cytometry, cytokine measurements, co-immunoprecipitation, and ubiquitination/proteasome-degradation assays.

Results

The meta-analysis estimated a small, non-significant pooled difference in CD36 expression in bulk PBMC between the MDD and HC groups (SMD = 0.043, 95% CI −0.144 to 0.231). PBMC scRNA-seq revealed CD36 upregulation mainly in myeloid cells, accompanied by alterations in inflammatory genes and pathways. In CRS mice, myeloid CD36 levels increased in the liver and spleen, whereas Sigma-1R activation reduced CD36, lowered IL-6 and TNF-α, and improved depression-like behaviors. Mechanistically, Sigma-1R interacted with CD36 and promoted K48-linked ubiquitination and proteasome-dependent degradation. TRIM28 was identified as the E3 ubiquitin ligase mediating Sigma-1R–induced CD36 K48-linked ubiquitination, with K469 and K472 serving as critical ubiquitination sites. Knockdown of Sigma-1R in cells attenuated CD36 K48-linked ubiquitination. In vivo, pharmacological blockade with BD-1047 attenuated CD36 downregulation and associated effects, supporting Sigma-1R involvement.

Conclusions

Our study identifies the myeloid Sigma-1R–CD36 axis in MDD and demonstrates that Sigma-1R promotes CD36 proteasome-dependent degradation via TRIM28-dependent K48-linked ubiquitination. This pathway suggests that CD36 in peripheral myeloid subsets may serve as a measurable immune indicator and supports Sigma-1R–CD36 modulation as a potential therapeutic strategy to mitigate inflammation-associated depressive phenotypes.