T-2 toxin induces glycometabolic reprogramming in chondrocytes via a MALAT1/p38‑mediated ceRNA regulatory axis.

Abstract

T-2 toxin is a widely distributed dietary mycotoxin and a key environmental driver of Kashin-Beck disease (KBD), yet the molecular events linking exposure to cartilage injury remain incompletely defined. We examined the chondrotoxic mechanism of T-2 toxin through a MALAT1/miR-15b-5p/MAP2K3 competing endogenous RNA (ceRNA) axis across cellular, animal and human levels. Rat models of graded T-2 toxin exposure, combined with mRNA and miRNA sequencing identified affected pathways and candidate non-coding RNAs. In C28/I2 human chondrocytes, dual-luciferase and rescue experiments characterized the targeting relationships and functional consequences of the axis. The p38 inhibitor BIRB796 and exogenous insulin were administered to rats, and a 1:1:1 frequency-matched case-control study in a KBD-endemic area assessed clinical relevance. T-2 toxin increased chondrocyte MALAT1, which sponged miR-15b-5p and relieved its repression of MAP2K3, leading to sustained p38 MAPK hyperactivation and concurrent extracellular matrix degradation and glycometabolic reprogramming. p38 inhibition or insulin supplementation attenuated T-2 toxin-induced cartilage degeneration and glucose dysregulation in rats. In humans, elevated serum lactate and peripheral-blood MALAT1 were independently associated with both KBD and osteoarthritis. These findings expand the molecular network underlying T-2 toxin chondrotoxicity and provide candidate biomarkers for the health-risk assessment of mycotoxin exposure and prevention of environment-related osteoarthropathy.