Intracellular lactic acidosis reprograms glycolysis and mitochondrial anaplerosis in cancer cells

Intracellular lactic acidosis, a metabolic state newly defined in this study, is characterized by a coupled increase in intracellular lactate and proton concentrations, resulting in higher levels inside cancer cells than outside. This finding expands the Warburg paradigm: lactic acidosis is not merely extracellular but intracellular, reshaping metabolism through direct biochemical mechanisms. Acidic pH and elevated lactate jointly suppress glycolysis by inhibiting HK, PFK1, and GAPDH, enforcing a low-flux, energy-efficient state. Meanwhile, pyruvate enters the tricarboxylic acid cycle through a pyruvate - lactate -export - reimport - lactate - pyruvate cycle that both fuels mitochondrial metabolism and maintains lactic acidosis intracellularly and extracellularly. Lactic acidosis also reprograms anaplerosis by promoting lactate-derived oxaloacetate formation and reducing glutamine dependence. Together, these findings establish lactic acidosis as an active regulator of cancer metabolism, revealing a distinct metabolic state. This coupled lactate-proton state drives coordinated metabolic reprogramming across glycolysis and mitochondrial metabolism, representing a fundamental tumor adaptation that may be exploited to disrupt cancer metabolic resilience.