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Small bioactive peptides have emerged as promising eco-friendly plant immunomodulators with low resistance risk for sustainable crop disease control. Here, we identified cyclic dipeptide cyclo(Val-Pro) as a potential plant immunomodulator with no direct fungicidal activity, which effectively conferred robust rice resistance to M. oryzae via promoting host intrinsic defense responses. Pre-treatment with cyclo(Val-Pro) activated salicylic acid (SA)- and jasmonic acid (JA)-mediated innate immunity, triggered reactive oxygen species (ROS) accumulation and callose deposition, and modulated core circadian clock genes in rice leaves. Transcriptomic and metabolomic analysis revealed that optimal blast resistance efficacy by cyclo(Val-Pro) pre-treatment at 14:00 was associated with circadian clock regulation and metabolic reprogramming. Specifically, cyclo(Val-Pro) rewired phenylpropanoid and tryptophan metabolism in rice leaves, and tryptamine was validated as a key functional downstream metabolite.<\/jats:p>","DOI":"10.1021\/acs.jafc.6c07885","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T16:02:13Z","timestamp":1789574533000},"page":"30027-30041","source":"Crossref","is-referenced-by-count":0,"title":["Cyclo(Val-Pro),\na Potential Plant Immunomodulator,\nConfers Rice Blast Resistance via Circadian-Clock-Modulated Immune\nActivation and Metabolic Reprogramming"],"prefix":"10.1021","volume":"74","author":[{"given":"Xinqing","family":"Wu","sequence":"first","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuo","family":"Cheng","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenjie","family":"Yu","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Song","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyan","family":"Sun","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2030-3813","authenticated-orcid":true,"given":"Tao","family":"Lu","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0807-9991","authenticated-orcid":true,"given":"Haifeng","family":"Qian","sequence":"additional","affiliation":[{"name":"Shaoxing University , , ,","place":["Shaoxing, China, 312000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiushi","family":"Song","sequence":"additional","affiliation":[{"name":"Nanjing Agricultural University , , ,","place":["Nanjing, China, 210095"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3351-3075","authenticated-orcid":true,"given":"Zhengwei","family":"Fu","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310032"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7738-5971","authenticated-orcid":true,"given":"Yinhua","family":"Ni","sequence":"additional","affiliation":[{"name":"Zhejiang University of Technology , , ,","place":["Hangzhou, China, 310032"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"issue":"1","key":"2026093009075427100_cit1","doi-asserted-by":"publisher","first-page":"4146","DOI":"10.1038\/s41467-023-39880-w","article-title":"A protein kinase coordinates\ncycles of autophagy and glutaminolysis in invasive hyphae of the fungus\nMagnaporthe oryzae within rice cells","volume":"14","author":"Li","year":"2023","journal-title":"Nat. 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Food Chem."},{"issue":"9","key":"2026093009075427100_cit25","doi-asserted-by":"publisher","first-page":"2810","DOI":"10.1111\/pce.14648","article-title":"B-Box proteins BBX28 and BBX29 interplay with\nPSEUDO-RESPONSE REGULATORS to fine-tune circadian clock in Arabidopsis","volume":"46","author":"Yu","year":"2023","journal-title":"Plant Cell Environ."},{"issue":"8","key":"2026093009075427100_cit26","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1016\/j.molp.2015.03.003","article-title":"Circadian\nClock Genes Universally\nControl Key Agricultural Traits","volume":"8","author":"Bendix","year":"2015","journal-title":"Mol. Plant"},{"issue":"4","key":"2026093009075427100_cit27","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1111\/jipb.13230","article-title":"Circadian clock in plants:\nLinking timing to fitness","volume":"64","author":"Xu","year":"2022","journal-title":"J. Integr. 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Plant Biol."},{"issue":"4","key":"2026093009075427100_cit31","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1111\/imm.13747","article-title":"Circadian\nrhythm regulation in the\nimmune system","volume":"171","author":"Ding","year":"2024","journal-title":"Immunology"},{"issue":"30","key":"2026093009075427100_cit32","doi-asserted-by":"publisher","first-page":"9166","DOI":"10.1073\/pnas.1511182112","article-title":"Spatial and temporal\nregulation of biosynthesis of the plant immune signal salicylic acid","volume":"112","author":"Zheng","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"1","key":"2026093009075427100_cit33","doi-asserted-by":"publisher","first-page":"1538","DOI":"10.1038\/s41467-025-56787-w","article-title":"A pathogen effector\nHaRxL10 hijacks the circadian clock component CHE to perturb both\nplant development and immunity","volume":"16","author":"Fu","year":"2025","journal-title":"Nat. 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Agric. Food Chem."},{"issue":"1","key":"2026093009075427100_cit40","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1017\/S0021859605005708","article-title":"Crop losses\nto pests","volume":"144","author":"Oerke","year":"2006","journal-title":"Journal of Agricultural Science"},{"issue":"3","key":"2026093009075427100_cit41","doi-asserted-by":"publisher","first-page":"430","DOI":"10.1038\/s41559-018-0793-y","article-title":"The global burden of\npathogens and pests on major food crops","volume":"3","author":"Savary","year":"2019","journal-title":"Nat.\nEcol Evol"},{"issue":"3","key":"2026093009075427100_cit42","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.tibtech.2008.12.002","article-title":"Against the grain: safeguarding rice\nfrom rice blast\ndisease","volume":"27","author":"Skamnioti","year":"2009","journal-title":"Trends Biotechnol."},{"issue":"6, Part 2","key":"2026093009075427100_cit43","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1016\/j.biotechadv.2015.01.004","article-title":"Bio-based resistance\ninducers for sustainable plant protection against pathogens","volume":"33","author":"Burketova","year":"2015","journal-title":"Biotechnol. 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Food Chem."},{"issue":"30","key":"2026093009075427100_cit46","doi-asserted-by":"publisher","first-page":"16708","DOI":"10.1021\/acs.jafc.4c02063","article-title":"Hydrolyzed Chicken Meat\nExtract and Its Bioactive Cyclopeptides Protect Neural Function by\nAttenuating Inflammation and Apoptosis via PI3K\/AKT and AMPK Pathways","volume":"72","author":"Ni","year":"2024","journal-title":"J. Agric. Food Chem."},{"key":"2026093009075427100_cit47","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbi.2021.102030","article-title":"PTI-ETI crosstalk: an\nintegrative view of plant immunity","volume":"62","author":"Yuan","year":"2021","journal-title":"Curr. 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Sci."},{"key":"2026093009075427100_cit50","doi-asserted-by":"publisher","first-page":"358","DOI":"10.3389\/fpls.2014.00358","article-title":"The role of the secondary\ncell wall in plant resistance to pathogens","volume":"5","author":"Miedes","year":"2014","journal-title":"Front Plant Sci."},{"key":"2026093009075427100_cit51","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1146\/annurev-arplant-042811-105439","article-title":"The shikimate pathway\nand aromatic amino Acid biosynthesis\nin plants","volume":"63","author":"Maeda","year":"2012","journal-title":"Annu. Rev. 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