N6-methyladenosine (m6A) modification plays a crucial role in pain regulation by modulating pain-related gene expression. The cerebrospinal fluid-contacting nucleus (CSF-contacting nucleus) is closely associated with pain, and downregulation of P2X4 receptor (P2X4R) expression in this region alleviates hyperalgesia. However, the relationship between m6A modification and P2X4R in CSF-contacting nucleus remains unclear. This study aims to investigate the role and potential mechanisms of the m6A demethylase fat mass and obesity-associated protein (FTO) and P2X4R in neuropathic pain (NP) induced by spared nerve injury (SNI) in male mice. We observed decreased m6A levels and upregulated FTO expression in the CSF-contacting nucleus of SNI mice. FTO was primarily expressed in neurons of the CSF-contacting nucleus, with symmetrical distribution across its bilateral regions. In CSF-contacting nucleus, FTO overexpression reduced m6A methylation and promoted pain, while FTO inhibition increased m6A levels and alleviated pain hypersensitivity. The administration of the FTO inhibitor meclofenamic acid (MA) into CSF-contacting nucleus alleviated pain. FTO regulated the expression of P2rx4 mRNA and protein in CSF-contacting nucleus. Furthermore, P2rx4 mRNA is a downstream target of FTO-mediated m6A demethylation. In summary, the m6A demethylase FTO contributes to NP by upregulating the expression of P2rx4 mRNA and protein through mediating m6A demethylation of P2rx4 mRNA. Therefore, the m6A demethylase FTO in CSF-contacting nucleus may represent a novel therapeutic target for NP.

01 Jun 2025·Biomaterials

Targeting m6A demethylase FTO to heal diabetic wounds with ROS-scavenging nanocolloidal hydrogels

Article

Author: Xiao, Zecong ; Qin, Si ; Meng, Jianfu ; Cai, Yuxiong ; Deng, Shaohui ; Zeng, Kang ; Luo, Zhipeng ; Li, Li ; Xia, Laixin ; Wang, Mengying ; Xue, Xiaowen ; Li, Changxing ; Zheng, Zhaoping ; Zheng, Xinyao ; Dai, Wei ; Xu, Rui ; Gan, Ziqi ; Li, Yuan ; Xiao, Shan

Chronic diabetic wounds are a prevalent and severe complication of diabetes, contributing to higher rates of limb amputations and mortality. N6-methyladenosine (m⁶A) is a common RNA modification that has been shown to regulate tissue repair and regeneration. However, whether targeting m⁶A could effectively improve chronic diabetic wound healing remains largely unknown. Here, we found a significant reduction in mRNA m⁶A methylation levels within human diabetic foot ulcers, and the expression level of fat mass and obesity-associated protein (FTO) was significantly increased. We identified that m⁶A modifies the RNA of matrix Metalloproteinase 9 (MMP9), a key factor in diabetic wound healing, to regulate its expression. Importantly, we developed a ROS-scavenging nanocolloidal hydrogel loaded with an FTO inhibitor to increase the m⁶A level of MMP9 RNA in wounds. The hydrogel can effectively accelerate wound healing and skin appendage regeneration in streptozotocin-induced type I diabetic rats at day 14 (approximately 98 % compared to 76.98 % in the control group) and type II diabetic db/db mice at day 20 (approximately 93 % compared to 60 % in the control group). Overall, our findings indicate that targeting m⁶A with ROS-scavenging hydrogel loaded with FTO inhibitor may be an effective therapeutic strategy for diabetic wound healing.

01 May 2025·European Journal of Medicinal Chemistry

Development of 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors showing potent antileukemia activities

Article

Author: Wang, Zhen ; Hu, Xinyi ; Xia, Wenyang ; Liu, Lu ; Dong, Ze ; Yang, Cai-Guang ; Huang, Yue ; Song, Xiaomin ; Li, Ming ; Zhang, Xi ; Zhang, Deyan

Fat mass and obesity-associated protein (FTO) is the first discovered RNA N⁶-methyladenosine (m⁶A) demethylase. The highly expressed FTO protein is required to trigger oncogenic pathways in acute myeloid leukemia (AML), which makes FTO a promising antileukemia drug target. In this study, we identify 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors with good antileukemia activity. We replaced the phenyl A-ring in FB23, the first-generation of FTO inhibitor, with five-membered heterocycles and synthesized a new class of FTO inhibitors. Compound 12o/F97 shows strong enzymatic inhibitory activity and potent antiproliferative activity. 12o/F97 selectively inhibits m⁶A demethylation by FTO rather than ALKBH5, and has minimal effect on m¹A demethylation by ALKBH3. Additionally, 12o/F97 increases the protein levels of RARA and ASB2, while decreasing that of MYC in AML cell lines. Lastly, 12o/F97 exhibits antileukemia activity in a xenograft mice model without significant side-effects. The identification of 3-arylaminothiophenic-2-carboxylic acid derivatives as new FTO inhibitors not only expands the chemical space but also holds potential for antileukemia drug development.

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Indication	Highest Phase	Country/Location	Organization	Date
Non-Small Cell Lung Cancer	Preclinical	United States	Stanford University	29 Apr 2025

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