Supplementary Materials

The PDF file includes:

• Materials and Methods
• Fig. S1. Experimental validation of the FTO-entacapone interaction and entacapone target selectivity assessment.
• Fig. S2. Crystal complex structures of FTO bound with different types of inhibitors.
• Fig. S3. Dose-response effect of entacapone on the body weight of DIO mice.
• Fig. S4. Generation and phenotypic measurements of liver-specific Fto knockout mice.
• Fig. S5. Hepatic Fto regulates gluconeogenesis in the liver.
• Fig. S6. FTO-FOXO1 regulatory axis modulates G6PC and PCK1 expression in a hepatic cell line.
• Fig. S7. Hepatic Fto knockdown in db/db mice and enzymatic activity of FTO R96A mutant protein.
• Fig. S8. Characterization of m⁶A modifications and changes in gene expression in mouse adipose tissues.
• Fig. S9. Generation, RNA-seq analysis, and phenotypic analysis of Foxo1-Mut mice with the Foxo1 synonymous mutation at the Foxo1–m⁶A-2 site.
• Fig. S10. Proposed FTO-FOXO1 regulatory axis in adipose tissue and liver.
• Table S1. Statistics on data collection and structure refinement of FTO-inhibitor complex structures.
• Table S2. Structures and FTO enzymatic inhibition activities of 19 selected compounds from virtual screening.
• References (62–78)

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Other Supplementary Material for this manuscript includes the following:

• Data file S1 (Microsoft Excel format). Summary of all reported data values.