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Enhancing nutritional supply has emerged as a potential strategy for honeybees to enhance stress resistance. However, the underlying molecular mechanisms remain poorly understood. This study investigated the role of leucine (Leu) in regulating antioxidant responses in honeybees (Apis mellifera L.), with a focus on the involvement of sestrin and the Target of Rapamycin (TOR) signaling pathway. The results showed that Leu supplementation activated the TOR signaling pathway and upregulated sestrin expression, leading to enhanced antioxidant capacity and reduced reactive oxygen species (ROS) levels. Silencing sestrin disrupted antioxidant homeostasis, increased stress susceptibility, and caused midgut damage, confirming its essential role in oxidative stress resistance. Notably, inhibition of TOR did not prohibit the protective effects of Leu, suggesting that sestrin, rather than TOR, serves as a key mediator. Furthermore, Leu fine-tuned antioxidant responses under different stress conditions through sestrin. Overall, this study demonstrates that Leu and sestrin play a central role in maintaining antioxidant homeostasis and provide a theoretical basis for nutritional strategies to improve honeybee health and stress resilience.<\/jats:p>","DOI":"10.3390\/biology15141124","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T13:16:28Z","timestamp":1783689388000},"page":"1124","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Leucine Enhances Stress Resistance in Honeybees (Apis mellifera L.) by Modulating Sestrin-Dependent Antioxidant Responses"],"prefix":"10.3390","volume":"15","author":[{"given":"Zhe","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Animal Science, Shandong Agricultural University, Tai\u2019an 271017, China"},{"name":"Key Laboratory of Efficient Utilization of Non-Grain Feed Resources (Co-Construction by Ministry and Province), Shandong Agricultural University, Tai\u2019an 271017, China"},{"name":"Shandong Provincial Key Laboratory of Animal Nutrition and Efficient Feeding, Tai\u2019an 271017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenguo","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Shandong Agricultural University, Tai\u2019an 271017, China"},{"name":"Key Laboratory of Efficient Utilization of Non-Grain Feed Resources (Co-Construction by Ministry and Province), Shandong Agricultural University, Tai\u2019an 271017, China"},{"name":"Shandong Provincial Key Laboratory of Animal Nutrition and Efficient Feeding, Tai\u2019an 271017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Shandong Agricultural University, Tai\u2019an 271017, China"},{"name":"Key Laboratory of Efficient Utilization of Non-Grain Feed Resources (Co-Construction by Ministry and Province), Shandong Agricultural University, Tai\u2019an 271017, China"},{"name":"Shandong Provincial Key Laboratory of Animal Nutrition and Efficient Feeding, Tai\u2019an 271017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongfang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Shandong Agricultural University, Tai\u2019an 271017, China"},{"name":"Key Laboratory of Efficient Utilization of Non-Grain Feed Resources (Co-Construction by Ministry and Province), Shandong Agricultural University, Tai\u2019an 271017, China"},{"name":"Shandong Provincial Key Laboratory of Animal Nutrition and Efficient Feeding, Tai\u2019an 271017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2009-1707","authenticated-orcid":false,"given":"Xuepeng","family":"Chi","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Shandong 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baohua","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Animal Science, Shandong Agricultural University, Tai\u2019an 271017, China"},{"name":"Key Laboratory of Efficient Utilization of Non-Grain Feed Resources (Co-Construction by Ministry and Province), Shandong Agricultural University, Tai\u2019an 271017, China"},{"name":"Shandong Provincial Key Laboratory of Animal Nutrition and Efficient Feeding, Tai\u2019an 271017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"ref_1","first-page":"1","article-title":"Progress and future of pyrethroids","volume":"Volume 314","author":"Katsuda","year":"2012","journal-title":"Pyrethroids"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S0898-6568(02)00085-2","article-title":"Voltage-gated sodium channels as primary targets 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