Dongguang Guo

T-2 toxin (T-2), a potent immunotoxic trichothecene, induces severe thymic injury and immune dysfunction. Building on our identification of the ROS-NF-κB-NLRP3 axis, mitochondrial involvement remains poorly understood. Using murine and thymic epithelial cell models, we show that T-2 induces mitochondrial damage, activating PINK1-Parkin-mediated mitophagy that is adaptive but insufficient to maintain mitochondrial homeostasis. Inhibition of mitophagy by 3-methyladenine or Parkin silencing further compromised mitochondrial membrane potential by ∼34% and ∼22% versus T-2, respectively, accompanied by elevated intracellular ROS levels. Chlorogenic acid (CGA) ameliorated thymic atrophy, as evidenced by a ∼62% increase in thymus index versus T-2, enhanced PINK1-Parkin mitophagy, and alleviated oxidative, inflammatory, and apoptotic damage. Mechanistically, CGA modulated the KEAP1/SIRT1/AMPKα1 network, linking redox regulation to mitochondrial quality control, and its protective effects were largely abolished by PINK1 knockdown. Collectively, these findings establish insufficient mitophagy as a key driver of T-2 immunotoxicity and support CGA as a mitochondria-targeted dietary modulator.

Thymic epithelial cells (TECs) are critical for thymic structure and function, yet the impact of T-2 toxin (T-2) on TECs and related molecular pathways remains unclear. This study sheds light on the mechanisms of T-2-induced TEC damage, focusing on the ROS-NF-κB-NLRP3 signaling axis. The in vivo and in vitro analyses suggest that T-2 induces TEC injury through ROS-driven NLRP3 inflammasome activation, NF-κB signaling, inflammation, and apoptosis. Molecular docking analysis verified the binding of T-2 to critical components involved in oxidative stress, inflammatory signaling pathways, and apoptosis. These findings were further supported by therapeutic interventions targeting ROS and NLRP3. N-acetylcysteine (NAC) effectively reduced ROS levels, suppressed NF-κB signaling, inhibited NLRP3 activation, and mitigated inflammation and apoptosis, effects mirrored by the NLRP3 inhibitor MCC950, emphasizing the critical role of ROS-mediated NLRP3 inflammasome activation through NF-κB signaling in T-2-induced TEC damage. Concurrently, inhibition of the NF-κB signaling further suppressed ROS levels, NLRP3 inflammasome activation, and apoptosis in MTEC1 cells, emphasizing the pivotal function of the ROS-NF-κB-NLRP3 axis in the pathogenesis of T-2-induced thymic injury. Our study offers an in-depth insight into the mechanisms driving T-2-induced immunotoxicity and identifies potential therapeutic strategies targeting these pathways to mitigate thymic injury and preserve immune function.

MiR-195 has been implicated in inhibiting cell proliferation in different types of tumors. Whether it contributes to the process of thymic epithelial cells (TECs) proliferation remains unclear. In this study, we found that miR-195a-5p was highly up-regulated in the TECs isolated from the aging mice. Further experiments showed that miR-195a-5p mimic transfection inhibited the proliferation of mouse medullary thymic epithelial cell line 1 (MTEC1), whereas the transfection of miR-195a-5p inhibitor in MTEC1 had the opposite effect. In addition, miR-195a-5p had no obvious effect on MTEC1 apoptosis. Furthermore, Smad7, a negative regulator of transforming growth factor β pathway, was confirmed as a direct target of miR-195a-5p by luciferase assays. Taken together, our results indicate that miR-195a-5p inhibits MTEC1 proliferation, at least in part, via down-regulation of Smad7.