Ammonia indirectly drives PLOD2 expression through HIF-1α stabilization

PLOD2 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2) represents a critical node in cancer biology, serving as both a key regulator of the tumor microenvironment and a promising therapeutic target. PLOD2 is consistently upregulated across diverse solid tumors, driven primarily by three interconnected pathways: hypoxia (HIF-1α), growth factors (TGF-β), and metabolic stress.

The clinical significance extends beyond mere prognostication: PLOD2 elevation actively promotes cancer progression through collagen cross-linking, ECM stiffening, and metastasis facilitation. High PLOD2 expression is a significant negative prognostic marker consistently associated with reduced overall and recurrence-free survival. For example, in hepatocellular carcinoma, it correlates with a ~15-20 month reduction in median survival and a drop in 5-year survival rates from 55% to 25%. It is linked to specific aggressive features like liver metastasis in colorectal cancer and invasive growth in glioblastoma.

A positive feedback loop exists wherein ammonia stabilizes HIF-1α to induce PLOD2 expression, and PLOD2-derived ammonia sustains this signal, creating a self-amplifying axis of tumor progression.

PLOD2 produces ammonia, ammonia stabilizes HIF-1α, and HIF-1α in turn drives more PLOD2 expression.