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Background <p>Major depressive disorder (MDD) pathogenesis is associated with immune-inflammatory dysregulation. This study investigated the mechanistic role of caspase-1-mediated inflammatory pathways in MDD, exploring their therapeutic targeting potential and clinical predictive utility.</p> Methods <p>Peripheral blood levels of caspase-1, IL-1β, and IL-10&#xa0;were assessed&#xa0;in MDD patients,&#xa0;with longitudinal analysis&#xa0;of dynamic changes&#xa0;pre-/ post-antidepressant treatment. The predictive performance of the biomarker was validated using leave-one-out cross-validation (LOOCV) and receiver operating characteristic (ROC) analysis. A&#xa0;chronic unpredictable stress (CUS) rat model&#xa0;was established to evaluate&#xa0;the combined therapeutic effects&#xa0;of caspase-1 inhibitors&#xa0;with&#xa0;fluoxetine.</p> Results <p>Clinical data revealed that expression levels of caspase-1 and IL-1β exhibited an negative correlation with clinical treatment response in patients with MDD, with varying levels observed among patients with differing depression severity. In contrast, IL-10 expression demonstrated a positive correlation with therapeutic efficacy. Following treatment, significant reductions in caspase-1 and IL-1β levels were observed, concurrent with an elevation in IL-10. Caspase-1 demonstrated superior predictive accuracy for treatment response (0.8529 ± 0.3542), yielding an area under the ROC curve (AUC) of 0.72. In animal models, co-administration of a caspase-1 inhibitor with fluoxetine accelerated the onset of antidepressant effects, while simultaneously reducing peripheral blood caspase-1 and IL-1β levels.</p> Conclusions <p>The caspase-1/IL-1β axis contributes to MDD pathogenesis by disrupting the pro-inflammatory/anti-inflammatory balance. Its mediated immune response pattern represents a potential therapeutic target for novel antidepressant development. Combined caspase-1 modeling provides a reliable tool for predicting clinical efficacy in MDD, while caspase-1-targeted intervention strategies may overcome the limitation of slow onset of action associated with conventional therapies.</p>

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Analysis of the correlation between the expression levels of caspase-1/IL-1β in the peripheral blood and clinical efficacy in patients with first-episode MDD

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月7日

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  • Jing-Yang Gu,
  • Dong-Chuan Di,
  • Meng-Yue Gu,
  • Huan-Zhong Liu

摘要

Background

Major depressive disorder (MDD) pathogenesis is associated with immune-inflammatory dysregulation. This study investigated the mechanistic role of caspase-1-mediated inflammatory pathways in MDD, exploring their therapeutic targeting potential and clinical predictive utility.

Methods

Peripheral blood levels of caspase-1, IL-1β, and IL-10 were assessed in MDD patients, with longitudinal analysis of dynamic changes pre-/ post-antidepressant treatment. The predictive performance of the biomarker was validated using leave-one-out cross-validation (LOOCV) and receiver operating characteristic (ROC) analysis. A chronic unpredictable stress (CUS) rat model was established to evaluate the combined therapeutic effects of caspase-1 inhibitors with fluoxetine.

Results

Clinical data revealed that expression levels of caspase-1 and IL-1β exhibited an negative correlation with clinical treatment response in patients with MDD, with varying levels observed among patients with differing depression severity. In contrast, IL-10 expression demonstrated a positive correlation with therapeutic efficacy. Following treatment, significant reductions in caspase-1 and IL-1β levels were observed, concurrent with an elevation in IL-10. Caspase-1 demonstrated superior predictive accuracy for treatment response (0.8529 ± 0.3542), yielding an area under the ROC curve (AUC) of 0.72. In animal models, co-administration of a caspase-1 inhibitor with fluoxetine accelerated the onset of antidepressant effects, while simultaneously reducing peripheral blood caspase-1 and IL-1β levels.

Conclusions

The caspase-1/IL-1β axis contributes to MDD pathogenesis by disrupting the pro-inflammatory/anti-inflammatory balance. Its mediated immune response pattern represents a potential therapeutic target for novel antidepressant development. Combined caspase-1 modeling provides a reliable tool for predicting clinical efficacy in MDD, while caspase-1-targeted intervention strategies may overcome the limitation of slow onset of action associated with conventional therapies.