This review proposes that dynamic instability of neuronal lysosomal pH—driven by components such as V-ATPase, TMEM175, SLC7A11, ClC-7 and regulated by AMPK–mTORC1–TFEB—is a pathogenic mechanism in neurodegeneration and outlines strategies to restore lysosomal pH homeostatic resilience as a…

It identifies concrete molecular targets and pathways linked to autophagy, mitochondria–lysosome crosstalk, and neuroinflammation and highlights translational opportunities and challenges (biomarkers, neuron-subtype specificity, brain-penetrant modulators), making it highly actionable for…

The precise maintenance of the intra-lysosomal acidic microenvironment is vital for neuronal functions, including protein degradation, metabolic regulation, and organelle quality control. This review systematically elucidates the dynamic regulatory network governing neuronal lysosomal pH homeostasis, transcending the classical proton pump-leak model. We highlight a multifaceted system integrating vacuolar-type H+-ATPase (V-ATPase)-driven active proton pumping, proton leakage mediated by channels such as transmembrane protein 175 (TMEM175) and solute carrier family 7 member 11 (SLC7A11), membrane potential buffering by the Cl-/H+ exchanger ClC-7, and regulatory signaling pathways involving AMP-activated protein kinase (AMPK)-mechanistic target of rapamycin complex 1 (mTORC1)-transcription factor EB (TFEB). Crucially, pH dysregulation-manifesting as hyperacidification, alkalinization, or the increasingly recognized and potentially more deleterious phenomenon of dynamic instability-emerges as a fundamental pathogenic mechanism in neurodegenerative disorders like Alzheimer's disease (AD) and Parkinson's disease (PD). Such disruption impairs autophagic flux and mitochondria-lysosome crosstalk, triggering neuroinflammation and ultimately leading to neuronal dysfunction and death. Building upon these mechanistic insights, we discuss emerging therapeutic strategies, advocating a paradigm shift from merely correcting acid-base imbalance toward restoring intrinsic lysosomal pH homeostatic resilience. Finally, we outline critical challenges for clinical translation, including deciphering neuron subtype-specific mechanisms, identifying dynamic in vivo pH biomarkers, and developing brain-penetrant therapeutics. Overcoming these hurdles through interdisciplinary innovation is essential to advance lysosomal pH-targeted therapies into clinical practice.