Zhan Yuanyuan, Zeng Ning, Yu Jing, Wu Yiping, Zhu Keyu, Yang Zihui, Guo Xingjun, Zhang Qi, Liu Zeming
Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Invest Dermatol. 2025 Jun 6. doi: 10.1016/j.jid.2025.01.038.
Keloid is a cutaneous fibrotic disorder distinguished by uncontrolled dermal fibroblast proliferation and accumulation of collagen. N-methyladenosine (MA) modification is the most prevalent epitranscriptomic modification of eukaryotic mRNAs. MA modification participates in a variety of biological processes of cells by influencing the stability, translation efficiency, splicing, and transport of mRNAs. Recently, mA modification in keloids has garnered interest but is not fully understood. In this study, we discovered that keloids were in hyper-mA-modified status, and HNRNPC was overexpressed in keloid tissues and keloid fibroblasts. The knockdown of HNRNPC inhibited the migration and proliferation of keloid fibroblasts. Through RNA immunoprecipitation PCR and luciferase experiments, WDR77 was identified as an mA-dependent direct downstream target of HNRNPC. Furthermore, HNRNPC promoted the expression of WDR77 by increasing WDR77 stability, elevating the expression of TGF-β and SMAD3. In keloid xenograft nude mice, HNRNPC small interfering RNAs significantly limited keloid development with reduced WDR77 and TGF-β expression. Thus, our study revealed that HNRNPC regulated the pathological functions of keloid fibroblasts through the mA methylation of WDR77 mRNA and that the inhibition of HNRNPC limited keloid progression in vivo. Our results decipher an mA-related mechanism and potential therapeutic strategy for combating keloids.
瘢痕疙瘩是一种皮肤纤维化疾病，其特征在于真皮成纤维细胞不受控制的增殖和胶原蛋白的积累。N-甲基腺苷（m⁶A）修饰是真核生物mRNA中最普遍的表观转录组修饰。m⁶A修饰通过影响mRNA的稳定性、翻译效率、剪接和转运参与细胞的多种生物学过程。最近，瘢痕疙瘩中的m⁶A修饰引起了人们的关注，但尚未完全了解。在本研究中，我们发现瘢痕疙瘩处于高m⁶A修饰状态，且HNRNPC在瘢痕疙瘩组织和瘢痕疙瘩成纤维细胞中过表达。敲低HNRNPC可抑制瘢痕疙瘩成纤维细胞的迁移和增殖。通过RNA免疫沉淀PCR和荧光素酶实验，WDR77被鉴定为HNRNPC的m⁶A依赖性直接下游靶点。此外，HNRNPC通过增加WDR77稳定性、提高TGF-β和SMAD3的表达来促进WDR77的表达。在瘢痕疙瘩异种移植裸鼠中，HNRNPC小干扰RNA显著限制了瘢痕疙瘩的发展，同时WDR77和TGF-β表达降低。因此，我们的研究表明，HNRNPC通过WDR77 mRNA的m⁶A甲基化调节瘢痕疙瘩成纤维细胞的病理功能，并且抑制HNRNPC可在体内限制瘢痕疙瘩的进展。我们的结果揭示了一种与m⁶A相关的机制以及对抗瘢痕疙瘩的潜在治疗策略。
