show Abstracthide AbstractDrought and heat are major abiotic stresses frequently coinciding to threaten rice production. Although hundreds of stress-related genes have been identified in the past two decades, very few genes have been confirmed to confer resistance to multiple stresses in crops. Here we report ONAC023, identified through NAC-centered gene regulatory network and genetic association analyses, is a hub stress-regulator that integrates the regulations of both drought and heat tolerance in rice. The loss-of-function mutant of ONAC023 showed significantly increased sensitivity to drought and heat stresses, whereas the overexpression of ONAC023 confers drought and heat tolerance at both seedling and reproductive stages. Notably, drought and heat stresses activated the function of ONAC023 not only by the induction of ONAC023 transcript but also by the nuclear accumulation of ONAC023 protein through a remorin-importin-a-assisted translocation. Under drought or heat stress, ONAC023 can directly target and promote the expression of functionally diverse downstream genes, such as OsPIP2;7, PGL3, OsFKBP20-1b, and OsSF3B1, which are involved in various stress-responsive processes including water transport, reactive oxygen species homeostasis, and alternative splicing (AS). Furthermore, genome-wide AS profiling revealed that the loss of ONAC023 function led to alternation of the encoding outcomes of thousands of AS transcripts under drought and heat stresses. These results manifested that ONAC023 is fine tuned to positively regulate drought and heat tolerance through the integration of multiple stress-responsive processes. Our findings provide not only an underlying connection between drought and heat responses, but also a promising candidate for engineering multi-stress-resilient rice. Overall design: Drought or heat treated 4-leaf stage onac023 T-DNA insertion mutants and the derived wild type seedlings (DJ) were harvested for RNA-seq and ChIP-seq, in triplicate (two replicates for ChIP-Seq under the drought treatment), using Illumina Hiseq X Ten.