In rheumatoid arthritis, lactate accumulation in the synovial microenvironment induces histone lactylation, resulting in the stabilization of a pro-inflammatory, apoptosis-resistant phenotype in fibroblast-like synoviocytes and macrophages, which drives chronic joint destruction and disease flares despite immunosuppressive therapy.

In the inflamed joint, cells produce too much lactate due to low oxygen and high energy demand. This lactate enters the cell nucleus and attaches to histones, changing how genes are read. This modification turns on genes that make cells produce inflammatory signals and block their own death, causing them to multiply uncontrollably and destroy joint tissue. The same lactate also stabilizes key proteins that keep the inflammatory response active, making the joint remain inflamed even when medications try to calm it down.