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Background: Insects cannot synthesize sterols and must acquire them from food. The mechanisms underlying how insects uptake dietary sterols are largely unknown except that NPC1b, an integral membrane protein, has been shown to be responsible for dietary cholesterol uptake in Drosophila melanogaster. However, whether NPC1b orthologs in other insect species, particularly the economically important pests, function similarly remains to be determined., Results: In this study, we characterized the function of NPC1b in Helicoverpa armigera, a global pest that causes severe yield losses to many important crops. Limiting dietary cholesterol uptake to insects significantly inhibited food ingestion and weight gain. Compared to the wild-type H. armigera, the CRISPR/Cas9-edited NPC1b mutant larvae were incapable of getting adequate cholesterol and died in their early life stage. Gene expression profile and in situ hybridization analyses indicated that NPC1b was mainly expressed in the midgut where dietary cholesterol was absorbed. Expression of NPC1b was also correlated with the feeding life stages and was especially upregulated during early larval instars. Protein-ligand docking and sequence similarity analyses further demonstrated that NPC1b proteins of lepidopteran insects shared a relatively conserved cholesterol binding region, NPC1b_NTD, which, however, was highly divergent from bees-derived sequences., Conclusion: NPC1b was crucial for dietary cholesterol uptake and growth of H. armigera, and therefore could serve as an insecticide target for the development of a novel pest-management approach to control this economically significant insect pest with little off-target effect on bees and sterol-autotrophic animals. © 2020 Society of Chemical Industry., (© 2020 Society of Chemical Industry.)