Pathologic skin scarring presents a vast economic and medical burden. Unfortunately, the molecular mechanisms underlying scar formation remain to be elucidated. We used a hypertrophic scarring (HTS) mouse model in which Jun is overexpressed globally or specifically in α-smooth muscle or collagen type I–expressing cells to cause excessive extracellular matrix deposition by skin fibroblasts in the skin after wounding. Jun overexpression triggered dermal fibrosis by modulating distinct fibroblast subpopulations within the wound, enhancing reticular fibroblast numbers, and decreasing lipofibroblasts. Analysis of human scars further revealed that JUN is highly expressed across the wide spectrum of scars, including HTS and keloids. CRISPR-Cas9–mediated JUN deletion in human HTS fibroblasts combined with epigenomic and transcriptomic analysis of both human and mouse HTS fibroblasts revealed that JUN initiates fibrosis by regulating CD36. Blocking CD36 with salvianolic acid B or CD36 knockout model counteracted JUN-mediated fibrosis efficacy in both human fibroblasts and mouse wounds. In summary, JUN is a critical regulator of pathological skin scarring, and targeting its downstream effector CD36 may represent a therapeutic strategy against scarring.

中文翻译：

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JUN 在临床前体外和体内模型中通过 CD36 促进肥厚性皮肤瘢痕形成。

病理性皮肤瘢痕形成巨大的经济和医疗负担。不幸的是，疤痕形成的分子机制仍有待阐明。我们使用了肥厚性瘢痕（HTS）小鼠模型，其中 Jun 在 α-平滑肌或 I 型胶原蛋白表达细胞中整体或特异性过度表达，导致受伤后皮肤成纤维细胞过度细胞外基质沉积。Jun 过表达通过调节伤口内不同的成纤维细胞亚群、增加网状成纤维细胞数量和减少脂肪成纤维细胞来引发真皮纤维化。对人类疤痕的分析进一步表明，JUN 在广泛的疤痕中高度表达，包括 HTS 和瘢痕疙瘩。CRISPR-Cas9 介导的人类 HTS 成纤维细胞中的 JUN 缺失结合人类和小鼠 HTS 成纤维细胞的表观基因组和转录组分析表明，JUN 通过调节 CD36 启动纤维化。用丹酚酸 B 或 CD36 敲除模型阻断 CD36 可抵消 JUN 介导的人成纤维细胞和小鼠伤口中的纤维化功效。总之，JUN 是病理性皮肤瘢痕形成的关键调节因子，靶向其下游效应因子 CD36 可能代表一种针对瘢痕形成的治疗策略。