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 TCA cycle through a pyruvate -lactate -exportreimport -lactate -pyruvate cycle that both fuels mitochondrial metabolism and maintains lactic acidosis intracellularly and extracellularly.Lactic acidosis also reprograms anaplerosis by promoting lactatederived 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.