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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Wheat Fusarium head blight (FHB) is a globally prevalent and destructive fungal disease predominantly caused by Fusarium graminearum. Pydiflumetofen, a novel succinate dehydrogenase inhibitor (SDHI) fungicide, exhibits strong inhibitory activity against F. graminearum; however, the molecular regulatory mechanisms underlying the field-developed resistance in this pathogen remain poorly defined. In the present study, a field-evolved resistant isolate W24-039 and a sensitive isolate W24-016 were subjected to multi-omics analysis. The sequencing results identified compound mutations C89S\/A93V in SdhC2, and A21T\/S30F in SdhD of the resistant strain, which confer stable fungicide resistance without any detectable fitness costs. Physiological tests revealed that these target mutations sustain the homeostasis of succinate dehydrogenase (SDH) activity and intracellular ATP production. Following pydiflumetofen treatment, the sensitive isolate displayed remarkable declines in SDH activity, intracellular ATP content and deoxynivalenol (DON) biosynthesis, accompanied by markedly elevated cell membrane permeability. Transcriptomic sequencing uncovered 2221 differentially expressed genes (DEGs) in the sensitive strain under fungicide stress, and 2566 DEGs in the resistant isolate under the same conditions. The genes associated with detoxification and drug efflux, including cytochrome P450, glutathione S-transferase (GST), ABC and MFS transporters, were significantly upregulated in the resistant isolate. Metabolomic analysis indicated that differential metabolites were mainly enriched in the tricarboxylic acid (TCA) cycle, amino acid metabolism and membrane lipid biosynthesis pathways. The resistant strain maintained intact TCA cycle operation and accumulated high levels of pivotal metabolites such as phosphatidylcholine, unsaturated fatty acids and reduced glutathione. Integrated multi-omics analysis verified that the ABC transporter and glutathione metabolism pathways serve as core regulatory modules governing fungicide resistance. Collectively, F. graminearum develops resistance via the synergistic effects of SDH compound mutations, enhanced detoxification and efflux, and global metabolic remodeling, demonstrating that target-site mutation alone is not the sole driver of resistance, which is instead controlled by an intricate regulatory network involving multiple coordinated pathways. This study systematically characterizes the resistance regulatory network of F. graminearum against pydiflumetofen, and provides theoretical guidance for the rational application and sustainable field resistance management of this fungicide.<\/jats:p>","DOI":"10.3390\/ijms27156685","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:47:41Z","timestamp":1785145661000},"page":"6685","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcriptome and Metabolome Dissection of Multilayered Pydiflumetofen Resistance Mechanisms in Fusarium graminearum"],"prefix":"10.3390","volume":"27","author":[{"given":"Yun","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Quality and Safety for Agro-Products, Henan Academy of Agricultural Sciences, Zhengzhou 450002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Quality and Safety for Agro-Products, Henan Academy of Agricultural Sciences, Zhengzhou 450002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Yin","sequence":"additional","affiliation":[{"name":"Institute of Quality and Safety for Agro-Products, Henan Academy of Agricultural Sciences, Zhengzhou 450002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Cao","sequence":"additional","affiliation":[{"name":"Institute of Quality and Safety for Agro-Products, Henan Academy of Agricultural Sciences, Zhengzhou 450002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingni","family":"Cao","sequence":"additional","affiliation":[{"name":"Institute of Quality and Safety for Agro-Products, Henan Academy of Agricultural Sciences, Zhengzhou 450002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Feng","sequence":"additional","affiliation":[{"name":"Institute of Quality and Safety for Agro-Products, Henan Academy of Agricultural Sciences, Zhengzhou 450002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanghua","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Quality and Safety for Agro-Products, Henan Academy of Agricultural Sciences, Zhengzhou 450002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Quality and Safety for Agro-Products, Henan Academy of Agricultural Sciences, Zhengzhou 450002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxia","family":"Shang","sequence":"additional","affiliation":[{"name":"Institute of Quality and Safety for Agro-Products, Henan Academy of Agricultural Sciences, Zhengzhou 450002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongqi","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Quality and Safety for Agro-Products, Henan Academy of Agricultural Sciences, Zhengzhou 450002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihong","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Quality and Safety for Agro-Products, Henan Academy of Agricultural Sciences, Zhengzhou 450002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hu, C., Chen, P., Zhou, X., Li, Y., Ma, K., Li, S., Liu, H., and Li, L. 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