Targeting the TORC1/TORC2 Signaling Hub MoLst8 Cripples Fungal Pathogenesis and Reveals TF3 as a Novel Selective Inhibitor

Rice blast, caused by Magnaporthe oryzae, remains a primary threat to global food production, making the discovery of novel antifungal targets imperative. The Target of Rapamycin (TOR) signaling network is a prime target for therapeutic intervention, but the function of its central components in M. oryzae is not fully understood. In this study, we found that MoLst8 is indispensable for fungal growth, development, and virulence in M. oryzae. Genetic deletion of MoLST8 impairs fungal growth, conidiation, and virulence by disrupting TOR signaling, triggering excessive autophagy, and damaging plasma membrane integrity due to dysregulated lipid homeostasis. In addition, given the crucial role of MoAtg8 in M. oryzae, we identified a natural product Theaflavin-3,3′-digallate (TF3) that binds MoLst8 potently and suppresses fungal pathogenesis. Uniquely, TF3 functions as a branch-selective inhibitor, targeting TORC1 rather than TORC2. Our findings establish MoLst8 as a critical vulnerability and present TF3 as a lead compound for developing novel, target-specific fungicides.