Deng Xiaolin, Huang Yuan, Zhang Jinge, Chen Yuwen, Jiang Feifan, Zhang Zicai, Li Tanghua, Hou Lina, Tan Wanlong, Li Fei
Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, PR China.
Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, PR China.
Int Immunopharmacol. 2025 Feb 20;148:114119. doi: 10.1016/j.intimp.2025.114119. Epub 2025 Jan 23.
Bladder cancer (BCa), particularly muscle-invasive bladder cancer (MIBC), is associated with poor prognosis, partly because of immune evasion driven by M2 tumor-associated macrophages (TAMs). Understanding the regulatory mechanisms of M2 macrophage polarization via PRKN-mediated mitophagy and histone lactylation (H3K18la) is crucial for improving treatment strategies.
A single-cell atlas from 46 human BCa samples was constructed to identify macrophage subpopulations. Bioinformatics analysis and experimental validation, including ChIP-seq and lactylation modulation assays, were used to investigate the role of PRKN in M2 macrophage polarization and its regulation by H3K18la.
Single-cell analysis revealed distinct macrophage subpopulations, including M1 and M2 types. PRKN was identified as a critical regulator of mitophagy in M2 macrophages, supporting their immunosuppressive function. Bulk RNA-seq and gene intersection analysis revealed a set of mitophagy-related macrophage polarization genes (Mito_Macro_RGs) enriched in mitophagy and immune pathways. Pseudotime analysis revealed that PRKN was upregulated during the M1-to-M2 transition. siRNA-mediated PRKN knockdown impaired M2 polarization, reducing the expression of CD206 and ARG1. ChIP-seq and histone lactylation modulation confirmed that H3K18la enhanced PRKN expression, promoting mitophagy and M2 polarization and thereby facilitating immune suppression and tumor progression.
Histone lactylation regulated PRKN-mediated mitophagy, promoting M2 macrophage polarization and contributing to immune evasion in BCa.
膀胱癌（BCa），尤其是肌层浸润性膀胱癌（MIBC），预后较差，部分原因是M2肿瘤相关巨噬细胞（TAM）驱动的免疫逃逸。了解通过PRKN介导的线粒体自噬和组蛋白乳酸化（H3K18la）对M2巨噬细胞极化的调控机制对于改进治疗策略至关重要。
构建了来自46个人类BCa样本的单细胞图谱，以鉴定巨噬细胞亚群。采用生物信息学分析和实验验证，包括ChIP-seq和乳酸化调节试验，来研究PRKN在M2巨噬细胞极化中的作用及其受H3K18la的调控。
单细胞分析揭示了不同的巨噬细胞亚群，包括M1和M2型。PRKN被确定为M2巨噬细胞中线粒体自噬的关键调节因子，支持其免疫抑制功能。批量RNA-seq和基因交集分析揭示了一组富集在线粒体自噬和免疫途径中的线粒体自噬相关巨噬细胞极化基因（Mito_Macro_RGs）。伪时间分析显示，PRKN在M1向M2转变过程中上调。siRNA介导的PRKN敲低损害了M2极化，降低了CD206和ARG1的表达。ChIP-seq和组蛋白乳酸化调节证实，H3K18la增强了PRKN表达，促进了线粒体自噬和M2极化，从而促进了免疫抑制和肿瘤进展。
组蛋白乳酸化调节PRKN介导的线粒体自噬，促进M2巨噬细胞极化，并导致BCa中的免疫逃逸。
