Our previous work demonstrated that FL118 binds between H2A.X and coiled DNA, inhibiting DNA damage repair and ultimately inducing apoptosis in BC cells.[39] Contrary to conventional views on camptothecin and its derivatives, their classic target, TopI, may play a greater role in FL118‐associated adverse effects than in its antitumor efficacy.[40] Notably, our findings reveal that although A2 is structurally a camptothecin derivative, its potent antitumor activity in BC is achieved through specific targeting of MAD2L1. Here, MAD2L1 is linked to breast cancer.