Table 2.

Primary targets and antagonistic effect for T-2 organ toxicity.

Toxic targets	Model	Toxicity	The role of targets	Antagonistic effect	References
GLP-1 and CCK	Mice	Gastrointestinal toxicity	-GLP-1 and CCK promoted T-2-induced anorexia.	-The GLP-1 receptor antagonist Exendin9-39 or the CCK1/2 receptor antagonist SR27897 and L-365 caused attenuation of T-2-induced anorectic responses.	Wu et al. (2018)
GIP and NPY2	Nocturnal mouse food refusal model		-GIP and NPY2 are involved in T-2-induced anorexia.	-The GIP receptor antagonist Pro3GIP or NPY2 receptor antagonist JNJ-31020028 attenuated T-2-induced anorectic responses.	Sheng et al. (2018)
IRE1a	Human intestinal Caco-2 cells and HT-29 cells; mice		-IRE1α was a therapeutic target for intestinal damage caused by T-2.	-T-2 impaired the intestinal mucus barrier; IRE1α knock-down blocked T-2 to degrade mucin.	Lin et al. (2019)
5-HT and NK-1R	Nocturnal mouse food refusal model		-5-HT mediated T-2-induced anorexia.	-The 5-HT3 receptor antagonist granisetron or NK-1R antagonist Emend attenuated T-2-induced anorectic responses.	Sheng et al. (2019)
HIF-1α	RAW264.7 cells	Immunotoxicity	-HIF-1α is an important immunotoxicity target of T-2.	-HIF-1a inhibited T-2-mediated “immune evasion” process by negatively regulating PD-1/PD-L1 signaling.	You et al. (2022)
IGF-1R	Human C28/I2 chondrocytes and mouse hypertrophic ATDC5 chondrocytes	Skeletal toxicity	-Inhibition of IGF-1R may mediate chondrocyte death and extracellular matrix degeneration in T-2 induced-KBD.	-IGF-1R inhibitor (picropodophyllin) caused chondrocyte cell death of, decreased type II collagen expression and increased MMP-13 expression.	Zhang et al. (2021b)
MMP-10	Hypertrophic chondrocytes (ATDC5 cells)		-MMP-10 deficiency impaired endochondral osteogenesis in the pathogenesis of T-2-related KBD.	-MMP-10 knockdown exacerbated T-2-induced chondrocyte apoptosis, terminal differentiation, and death.	Zhang et al. (2022a)
Wnt/beta-catenin signaling	Mice		-T-2-induced femur lesion is associated with Wnt/β-linked protein signaling.	__	Zhang et al. (2022d)
MGMT	KBD patients and chondrocytes		-MGMT could provide a therapeutic target for T-2-induced KBD.	-DNA damage and apoptosis rates were increased in MGMT-silenced chondrocytes,	Zhang et al. (2022b)
TGF-βRs	Sprague Dawley rats; C28/I2 chondrocytes		-Inhibiting the expression of -TGF-βRs is a potential T-2-related KBD treatment.	-Blocking the TGF-βRs-Smad2 signaling pathway using GW788388 abrogated the effect of T-2 on upregulating MMP-13 expression.	Zhang et al. (2022g)
HSP47	C28/I2 and ATDC5 cells; rats.		-T-2 decreased the expression of HSP47, which mediated the reduction of type II collagen expression.	-Restoration of HSP47 expression may alleviate matrix degradation in chondrocytes.	Zhang et al. (2021a)
YAP	Rat chondrocyte		-T-2 increased total YAP protein, which played an important role in T-2-induced chondrocyte damage.	-YAP inhibitors alleviated chondrocyte damage.	Li et al. (2022a)
HMGB1	PC12 cell	Neurotoxicity	-HMGB1 played a critical role in T-2-stimulated PC12 cells simultaneously displayed apoptosis and inflammation.	-HMGB1's silence reduced T-2-mediated oxidative stress, apoptosis and neuroinflammatory outbreak.	Pei et al. (2021)
Nrf2	Human neuroblastoma SH-SY5Y cells		-Nrf2-mediated mitochondrial biogenesis contributed to T-2 -induced toxicity	-Nrf2 knockdown exacerbated T-2-induced cytotoxicity, oxidative stress, and mitochondrial dysfunction, as well as aggravated mitochondrial biogenesis impairment.	Pang et al. (2022)
HO-1	Mouse neuroblastoma-2a cells		__	-HO-1 inhibitor enhanced T-2-induced neurotoxicity.	Zhang et al. (2018)
NF-κB and MAPK	BV-2 cells		__	-Inhibitors of NF-κB and MAPK reversed T-2-induced microglia activation, thereby alleviating neurocytotoxicity.	Li et al. (2023)
CYP1A5	Chicken primary hepatocytes	Hepatotoxicity	-CYP1A5 can be significantly induced by T-2 in chicken primary hepatocytes and catalyze T-2 into a more toxic product, 3′–OH–T-2.	-CYP1A5 induction mediated by AhR enhanced the cytotoxicity of T-2 by reducing cell viability, activating oxidative stress and inducing DNA damage as well as apoptosis.	Liu et al. (2019)
CYP1A1	HepG2 cells		-Hepatotoxicity of T-2 might be related to the CYP1A1.	__	Ye et al. (2019)
SIRT1	HepG2 cells		-SIRT1 played an essential role in T-2-induced ROS production.	-The increase of ROS was linked to the upregulation of SIRT1 under T-2 exposure.	Ma et al. (2017)
FXR	Broiler chicken livers		-FXR played a hepatoprotection role in liver injury induced by T-2.	-Activated FXR promoted xenobiotic metabolism of T-2 and attenuated oxidative stress in broiler chicken liver.	Dai et al. (2020)
TET3	HepG2 cells		-TET3 may serve as a potential new target for toxicogenic detoxification.	-TET3-mediated CYP1A1 induction enhanced the cytotoxicity of T-2 toxin through inhibiting cell proliferation.	Zhu et al. (2023)
Nrf2	Mice	Nephrotoxicity	-Nrf2 pathway mediated T-2-induced nephrotoxicity by oxidative stress.	__	Zhang et al. (2021c)
PINK1/Parkin	C57BL/6N mice		-Knocking out Parkin inhibited the mitophagy.	-PINK1/Parkin-mediated mitophagy mitigates T-2-induced nephrotoxicity	Zhang et al. (2022e)
PERK	PK-15 cells		-PERK-mediated ER stress was involved in PK-15 apoptosis under T-2 exposure.	-The PERK inhibitor prevented the T-2-induced decrease in cell activity and apoptosis.	Liu et al. (2021a)
mTORC2	TM3 cells	Reproductive toxicity	-T-2 exposure induced apoptosis in TM3 cells by inhibiting mTORC2/AKT to promote Ca2+ production.	-BAPTA-AM (a Ca2+ chelator) and MHY1485 (an mTOR activator) could prevented T-2-induced TM3 cell apoptosis.	Wang et al. (2018)
PPAR-γ	Rats	Cardiomyopathy	-PPAR-γ has the potential to serve as an effective therapeutic target in T-2-induced cardiac fibrosis of rats.	-Increasing exogenous PPAR-γ play a role in relieving cardiac fibrosis caused by T-2.	Lu et al. (2021b)

5-HT = 5-hydroxytryptamine; AKT = protein kinase B; CCK = cholecystokinin; CYP1A5 = cytochrome P450 1A5; CYP1A1 = cytochrome P450 1A1; FXR = farnesoid X receptor; GLP-1 = glucagon-like peptide-17-36 amide; GIP = glucose-dependent insulinotropic polypeptide; HIF-1α = hypoxia-inducible factors-1 alpha; HMGB1 = high mobility group B1; HO-1 = heme oxygenase 1; HSP47 = heat shock protein 47; IRE1a = inositol-requiring enzyme 1 alpha; IGF-1R = insulin like growth factor 1 receptor; KBD = Kashin-Beck disease; MAPK = mitogen-activated protein kinase; MGMT = O6-methylguanine-DNA methyltransferase; MMP-10 = matrix metalloproteinase-10; MMP-13 = matrix metalloproteinase-13; mTORC2 = mammalian target of rapamycin complex 2; NF-κB = nuclear factor -kappa B; NK-1R = neurokinin-1 receptor; NPY2 = neuropeptide Y2; Nrf2 = nuclear factor erythroid 2 related factor 2; PINK1 = phosphatase and tensin homolog (PTEN)-induced putative kinase1; Parkin = E3 ubiquitin ligase PARK2; PD-1 = programmed cell death protein-1; PD-L1 = programmed cell death-ligand 1; PERK = protein kinase RNA-like ER kinase; PPAR-γ = peroxisome proliferator-activated receptor-γ; SIRT1 = silent information regulator sirtuin 1; TET3 = eleven translocation family protein 3; TGF-βRs = transforming growth factor-beta receptors; YAP = Yes-associated protein.