Pyruvate kinase M2 - linked metabolic pathways in pain modulation.

The glycolytic enzyme pyruvate kinase M2 (PKM2) is emerging as a crucial modulator of cancer cell proliferation and pain signaling. Pathological lactate accumulation causes tissue acidification, sensitizing pain pathways, in which PKM2 plays a central role. Evidence links PKM2 to both nociceptive and neuropathic pain via molecular cascades involving cyclooxygenase (COX)-1/2, interleukin (IL)-1β, and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) activation. Phosphorylated PKM2 enhances NFκB, STAT3, and ERK pathways, promoting inflammatory and neuronal sensitization. By integrating metabolic reprogramming with pain signaling, PKM2 represents a pivotal bridge between inflammation, neuronal excitation, and energy metabolism, offering promising therapeutic potential for managing complex pain-linked conditions.