《生命科学》 2026, 38(1): 194-206

自噬双向调节因子磷脂酶D：潜在的治疗靶点

肖 花¹ , 罗浩荡^1,2 , 高思琪¹ , 唐小茜¹ , 曾焱华^1,*

¹南华大学衡阳医学院基础医学院病原生物学研究所，衡阳 421001 ²南华大学衡阳医学院附属南华医 院，衡阳 421002

摘　要：

磷脂酶D （phospholipase D，PLD）水解磷脂酰胆碱生成的磷脂酸（phosphatidic acid，PA）作为重要的脂质第二信使，参与调控细胞膜脂质修饰、信号转导及囊泡运输等过程。自噬作为维持细胞内稳态的核心机制，通过清除异常组分和维持能量循环，在细胞生长、发育及代谢平衡中发挥重要作用。PLD对自噬具有双向调控能力，其调控方向受亚细胞定位、微环境信号（如营养状态）及疾病背景的显著影响。本文综述了PLD活性与自噬的相互作用网络，重点解析了两者在肿瘤、神经退行性疾病等疾病发生发展中的协同机制，以期为开发PLD小分子抑制剂精准治疗自噬相关疾病提供新的见解。

通讯作者：曾焱华 , Email:zengyihua21cn@usc.edu.cn

Bidirectional regulation of autophagy by PLD: a target for disease treatment

XIAO Hua¹ , LUO Hao-Dang^1,2 , GAO Si-Qi¹ , TANG Xiao-Qian¹ , ZENG Yan-Hua^1,*

¹Institute of Pathogenic Biology, School of Basic Medical Sciences, Hengyang Medical College, University of South China, Hengyang 421001, China ²The Affiliated Nanhua Hospital, Hengyang Medical College, University of South China, Hengyang 421002, China

Abstract:

Phospholipase D (PLD) is an essential enzyme in lipid metabolism that facilitates the hydrolysis of phosphatidylcholine, resulting in the production of phosphatidic acid (PA) and choline. PA serves as an important lipid second messenger, participating in the regulation of critical cellular processes such as membrane lipid modification, signal transduction, and vesicle trafficking. Autophagy is a fundamental and conserved intracellular degradation system, acting as a core mechanism for maintaining cellular homeostasis. It performs essential functions by clearing damaged components and recycling biomolecules, thereby playing a vital role in cell growth, development, and metabolic balance. The interaction between PLD-mediated lipid signaling and the autophagic pathway represents a significant cellular regulation with profound implications for both normal physiology and disease states. This review explores the complex, bidirectional role of phospholipase D (PLD) in regulating autophagy. The way PLD influences autophagic flux, whether it promotes or inhibits it, is not fixed but rather depends on specific contextual factors. These factors include the distinct subcellular localization of PLD′s major isoforms (PLD1 and PLD2), microenvironmental signals such as nutrient availability, and the particular pathological context. We summarize the intricate molecular network through which the PLD-PA axis exerts this dual control, detailing its interactions with central autophagy regulators, including the mTORC1 complex, the AMPK-ULK1 axis, and the VPS34-Beclin 1 core machinery. This positions PLD as a dynamic modulator capable of fine-tuning autophagy in response to varying cellular conditions. The dysregulation of PLD-mediated autophagy is strongly associated with the pathogenesis of multiple human diseases. PLD′s role exhibits clear disease-specific patterns: it can promote autophagic flux in glioblastoma and breast cancer, yet suppress it in others like cervical and colorectal cancer. In neurodegenerative disorders, including Alzheimer′s and Parkinson′s diseases, deficient PLD activity often contributes to impaired autophagy and the accumulation of toxic proteins. Moreover, altered PLD-autophagy signaling is associated with the progression of liver diseases and polycystic kidney disease. Therefore, the PLD-PA axis appears to be a promising target for therapy. The future development of isoform specific PLD modulators, strategically designed to correct the specific autophagic imbalance present in a given disease, offers a compelling avenue for the development of novel and precise therapeutic interventions.

Communication Author：ZENG Yan-Hua , Email:zengyihua21cn@usc.edu.cn