KIAA1429 promotes chondrocyte senescence and ferroptosis in osteoarthritis progression by facilitating m6A-mediated downregulation of USP3, and inhibition of KIAA1429 suppresses OA development in vitro and in vivo.
KIAA1429 expression was upregulated in chondrocytes treated with IL-1β to model osteoarthritis in vitro.
Inhibition of KIAA1429 impeded senescence in IL-1β-treated C28/I2 chondrocytes.
Inhibition of KIAA1429 impeded ferroptosis in IL-1β-treated C28/I2 chondrocytes.
KIAA1429 reduced USP3 mRNA expression through m6A methylation modification, suppressing its mRNA stability.
USP3 downregulation rescued the protective effects of KIAA1429 knockdown on IL-1β-induced chondrocyte senescence and ferroptosis.
KIAA1429 downregulation suppressed the development of OA in a mouse DMM (destabilization of the medial meniscus) model in vivo.
This research suggests that a protein called KIAA1429 plays a key role in driving the progression of osteoarthritis (OA), a common joint disease that causes cartilage breakdown. Using cartilage cells (chondrocytes) treated with an inflammatory molecule (IL-1β) to mimic OA conditions, the researchers found that KIAA1429 levels rise during OA-like stress. When KIAA1429 is active, it chemically tags the genetic message for another protein called USP3 — through a process called m6A methylation — causing that message to become unstable and USP3 levels to drop. This reduction in USP3 then leads to two harmful outcomes in chondrocytes: accelerated cellular aging (senescence) and a specific type of cell death called ferroptosis. When KIAA1429 was blocked, both of these damaging processes were reduced, and when USP3 was also blocked at the same time, the protective effects were reversed, confirming that USP3 is the key link in this chain. The researchers also tested their findings in living mice with surgically induced OA and found that reducing KIAA1429 activity slowed the development of the disease in the joint. This research suggests that the KIAA1429–USP3 pathway represents a previously unrecognized mechanism contributing to cartilage deterioration in osteoarthritis. Targeting this pathway — particularly by inhibiting KIAA1429 or restoring USP3 function — could potentially offer new therapeutic strategies for OA, though further research in humans would be needed before any clinical applications could be considered.
Ma B, Zhao J, Cheng C, Yang B. (2026). KIAA1429 promotes chondrocyte senescence and ferroptosis in osteoarthritis progression by facilitating m6A-mediated downregulation of USP3.. General physiology and biophysics. https://doi.org/10.4149/gpb_2026020