What is it about?
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.
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Why is it important?
This paper is important because it provides a mechanistic perspective on pain by positioning pyruvate kinase M2 (PKM2) as a critical link between cellular metabolism, inflammation, and nociceptive signaling. By integrating evidence on PKM2-mediated metabolic reprogramming, glycolysis, lactate accumulation, and downstream pathways such as ERK/MAPK, NF-κB, STAT3, COX, and pro-inflammatory cytokines, the review demonstrates how metabolic alterations can contribute to neuronal sensitization and the persistence of both nociceptive and neuropathic pain. Importantly, it moves beyond conventional neurotransmitter- and inflammation-centered models to highlight metabolic regulation as an emerging therapeutic dimension, while identifying PKM2 as a potentially druggable target for developing novel, mechanism-based interventions for chronic and difficult-to-treat pain conditions.
Perspectives
From my perspective, this paper is important because it reflects a shift in how we understand pain, moving beyond the conventional focus on neuronal and inflammatory signaling toward the emerging role of cellular metabolism. By exploring PKM2 as a molecular link between metabolic reprogramming, glycolysis, lactate accumulation, neuroinflammation, and nociceptive signaling, the review highlights how metabolic alterations may actively contribute to pain development and persistence. I believe this perspective is particularly valuable because it identifies PKM2 as a potentially druggable metabolic target and opens new possibilities for developing mechanism-based therapeutic strategies, especially for chronic and neuropathic pain where existing treatments remain inadequate.
Mr Lahanya Guha
Read the Original
This page is a summary of: Pyruvate kinase M2 – linked metabolic pathways in pain modulation, Drug Discovery Today, January 2026, Elsevier,
DOI: 10.1016/j.drudis.2025.104557.
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