Tomato yellow leaf curl virus (TYLCV) poses a serious threat to global tomato production. Current management strategies remain limited, highlighting the need for novel antiviral agents. In this study, we evaluated the efficacy of a newly synthesized pyrimidine–guanidine derivative, YYH-6, against TYLCV in tomato (Solanum lycopersicum cv. Micro-Tom) and investigated its underlying mechanisms. Foliar application of YYH-6 significantly reduced viral accumulation and alleviated disease symptoms. Transcriptomic analysis revealed that YYH-6 treatment upregulates defense-related pathways such as plant–pathogen interaction, MAPK signaling, and phenylpropanoid biosynthesis. Results of TRV-based virus-induced gene silencing (VIGS) further indicate that RPP13 and ALS2 function as important resistance genes induced by YYH-6. Activity-based protein profiling, LC–MS/MS, and reverse genetic verification by VIGS indicate that serine hydroxymethyltransferase and STI1 domain-containing proteins are potential target proteins of YYH-6 for TYLCV inhibition. Our findings demonstrate that YYH-6 suppresses TYLCV infection through multitarget modulation of host defense pathways, making it a promising candidate for sustainable management of tomato viral diseases.

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