Yao Yu-Xin, Yao Chen-Hao, Zhang Chao-Yang, Peng Xian-Zhi, Dai Shu, Yu Yu-Jie, Li Yan-Zhi, Zhang Sheng-Lin, Li Yun-Xia
State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu 611137, China.
School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
Am J Chin Med. 2025;53(2):523-542. doi: 10.1142/S0192415X2550020X. Epub 2025 Mar 27.
Acetaminophen (APAP)-induced liver injury (AILI) is a universal liver disease and the predominant cause of acute liver failure in clinical practice. Autophagy is a highly conserved intracellular degradation pathway, with accumulating evidence indicating its involvement in APAP hepatotoxicity. Notably, the serine/threonine AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/unc-51-like kinase 1 (ULK1) pathway serves as the most classical autophagy pathway and engages in autophagy activation. Thus, pharmacological activation of the AMPK/mTOR/ULK1 pathway has emerged as a critical strategy for addressing AILI. Chlorogenic acid (CGA), a main bioactive constituent isolated from Thunb., is an autophagy regulator with potential for AILI therapy. However, whether and how CGA modulates autophagy to antagonize AILI has not yet been elucidated. In the present study, we aim to explore the impact of CGA on AILI, as well as the underlying mechanisms and . The results demonstrated that CGA could protect the mice and LO2 cells from oxidative stress and liver injury induced by APAP. Regarding mechanisms, CGA activated the AMPK/mTOR/ULK1 pathway, thereby promoting autophagy. This was evidenced by the degradation of p62/SQSTM1 (hereafter referred to as p62), as well as the up-regulation of LC3B, ATG5, and Beclin1. It is worth noting that the aforementioned, CGA-provided beneficial effects were abrogated by pharmacological inhibition of AMPK with Compound C (CC, an AMPK inhibitor). These [Formula: see text] that CGA alleviates oxidative stress and liver injury induced by APAP, which is contingent upon the regulatory effect of CGA on the AMPK/mTOR/ULK1 axis.
对乙酰氨基酚（APAP）诱导的肝损伤（AILI）是一种常见的肝脏疾病，也是临床实践中急性肝衰竭的主要原因。自噬是一种高度保守的细胞内降解途径，越来越多的证据表明其参与了APAP的肝毒性作用。值得注意的是，丝氨酸/苏氨酸AMP激活蛋白激酶（AMPK）/雷帕霉素哺乳动物靶蛋白（mTOR）/unc-51样激酶1（ULK1）途径是最经典的自噬途径，参与自噬激活。因此，药理学激活AMPK/mTOR/ULK1途径已成为治疗AILI的关键策略。绿原酸（CGA）是从忍冬属植物中分离出的主要生物活性成分，是一种具有AILI治疗潜力的自噬调节剂。然而，CGA是否以及如何调节自噬以拮抗AILI尚未阐明。在本研究中，我们旨在探讨CGA对AILI的影响及其潜在机制。结果表明，CGA可以保护小鼠和LO2细胞免受APAP诱导的氧化应激和肝损伤。在机制方面，CGA激活了AMPK/mTOR/ULK1途径，从而促进自噬。这通过p62/SQSTM1（以下简称p62）的降解以及LC3B、ATG5和Beclin1的上调得到证实。值得注意的是，上述CGA提供的有益作用被化合物C（CC，一种AMPK抑制剂）对AMPK的药理学抑制所消除。这些结果表明，CGA减轻了APAP诱导的氧化应激和肝损伤，这取决于CGA对AMPK/mTOR/ULK1轴的调节作用。
