Li Huari, Wang Xueyi, Deng Yian, Liu Mingze, Li Wenjie, Wang Junjie, Zeng Cuiping, Dai Hanchuan
College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Wuhan 430070, Hubei Province, PR China; Department of Biochemistry and Molecular Biology, College of Laboratory Medicine, and Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, No.2600 Donghai Avenue, Bengbu 233030, Anhui Province, PR China.
College of Veterinary Medicine, Huazhong Agricultural University, No.1 Shizishan Street, Wuhan 430070, Hubei Province, PR China.
Int J Biol Macromol. 2025 Sep;321(Pt 3):146500. doi: 10.1016/j.ijbiomac.2025.146500. Epub 2025 Aug 4.
Acute lung injury (ALI) is a hypoxic respiratory insufficiency disease characterized by oxidative damage, inflammatory response, and autophagic cell death. Resveratrol (Res) modulates the autophagy activation and excessive autophagy inhibition to counteract oxidative stress, yet the latter mechanism has been vague. Herein, effects and regulatory mechanisms of Res on lung injury, inflammation, and autophagy/mitophagy were explored in lipopolysaccharide (LPS)-stimulated rats and RAW264.7 cells. Transcriptome data exhibited that, Res influenced oxidative stress, inflammation, apoptosis, necroptosis, proliferation, and migration probably through TNF/NF-kB-mediated phagosome and lysosome formations in ALI rats. In subsequent assays, Res significantly reversed the LPS-induced lung injury and mitochondrial dysfunction via activating the SIRT1/PGC-1α pathway. Also, Res reduced LPS-triggered inflammatory cytokines through restraining the TNF/NF-κB/JNK pathway. Importantly, Res attenuated excessive LC3/ATG5/p62-mediated autophagy and PINK1/Parkin-adjusted mitophagy, decreasing the autophagic flux by inactivating the NF-κB pathway. Thus, Res augmented anti-oxidative and anti-inflammatory effects most likely through ameliorating the excessive autophagy/mitophagy via two converging pathways (SIRT1/PGC-1α and TNF/NF-κB/JNK). Notably, Res down-regulated the DNMT2/TRDMT1 expression and probably adopted a similar binding pattern with plant flavonoids to block this enzyme. Altogether, these findings will provide a novel mechanism and therapeutic strategy for ALI or related lung diseases by Res-modulated autophagy/mitophagy inactivation and DNMT2/TRDMT1 inhibition.
急性肺损伤（ALI）是一种以氧化损伤、炎症反应和自噬性细胞死亡为特征的低氧性呼吸功能不全疾病。白藜芦醇（Res）可调节自噬激活和过度自噬抑制以对抗氧化应激，但其后者机制尚不清楚。在此，研究了Res对脂多糖（LPS）刺激的大鼠和RAW264.7细胞中肺损伤、炎症以及自噬/线粒体自噬的影响和调节机制。转录组数据显示，Res可能通过TNF/NF-κB介导的吞噬体和溶酶体形成影响ALI大鼠的氧化应激、炎症、凋亡、坏死性凋亡、增殖和迁移。在随后的实验中，Res通过激活SIRT1/PGC-1α途径显著逆转了LPS诱导的肺损伤和线粒体功能障碍。此外，Res通过抑制TNF/NF-κB/JNK途径降低了LPS触发的炎性细胞因子。重要的是，Res减弱了LC3/ATG5/p62介导的过度自噬和PINK1/Parkin调节的线粒体自噬，通过使NF-κB途径失活降低了自噬通量。因此，Res最有可能通过两条汇聚途径（SIRT1/PGC-1α和TNF/NF-κB/JNK）改善过度自噬/线粒体自噬，从而增强抗氧化和抗炎作用。值得注意的是，Res下调了DNMT2/TRDMT1的表达，并且可能采用与植物黄酮类似的结合模式来阻断该酶。总之，这些发现将为Res调节自噬/线粒体自噬失活和DNMT2/TRDMT1抑制为ALI或相关肺部疾病提供一种新的机制和治疗策略。
