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.
XIAO et al. (Thu,) studied this question.