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Illustration of ferroptosis therapy for the treatment of kidney cancer using Fe/Ni-LDH. GPX4: glutathione peroxidase 4, GSH: reduced glutathione, GSSG: oxidized glutathione, LOOH: lipid hydroperoxide, LOH: lipid alcohol. [Display omitted] • A general and facile method was proposed for synthesizing Fe/Ni-LDH to achieve apoptosis-enhanced and ferroptosis-involved cancer nanotherapy. • The Fe/Ni-LDH exhibited great ROS-generating catalytic activity for chemo-dynamic therapy, resulting in the apoptosis-induced cell death pathway, intracellular oxidative damage, and LPO accumulation to promote ferroptosis-involved cancer cell death. • The KEGG pathway enrichment and GSEA analyses of transcriptome sequencing indicated that ferroptosis was involved in Fe/Ni-LDH anti-tumor therapy. Nanocatalysts provide a platform for developing anti-tumor strategies by activating intratumoral chemical catalysis to produce highly toxic reactive oxygen species (ROS). However, the biological effect of nanocatalysts on tumor cells, which is pivotal for effective nanotherapy treatment, remains poorly understood. Herein, we present a general and facile method of synthesizing Fe/Ni-layered double hydroxides (LDHs) for enhanced apoptosis- and ferroptosis-induced cancer nano-therapy, as well as a potential mechanism underlying the anti-tumor effect based on transcriptome sequencing. An analysis of the chemical structure suggests that the Fe atoms interact strongly with the Ni atoms in Fe/Ni-LDH. Compared with Fe-OH and Ni-OH, Fe/Ni-LDH exhibited significantly better ROS-catalytic activity, with a V max of 5.015 × 10−2 μM·s−1, and generated massive amounts of •OH and O 2 •− radicals, enabling outstanding chemo-dynamic therapy. Both in vitro and in vivo experiments indicated a robust apoptosis-induced cell death pathway, increased intracellular oxidative stress, and accumulation of lipid peroxide (LPO), promoting ferroptosis-involved cancer-cell death, which was further confirmed by transcriptome sequencing. The Fe/Ni-LDH biocatalyst not only provides a robust nanoplatform for tumor suppression but also encourages further exploration and applications of nanobiocatalysts. [ABSTRACT FROM AUTHOR]