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To delineate the cell-type-specific mechanisms underlying neuronal hyperexcitability, we resolve the hyperexcitability of excitatory neurons across epileptic human brain trans-foci at single-cell resolution to identify the key drivers and potential diagnostic signatures. We constructed a comprehensive atlas encompassing 240,000 cells derived from the temporal cortex and hippocampus, detecting trans-regional cellular and molecular diversity. We further delineated dynamic trajectories, gene expression patterns, and functional reorganization across cell types. Using the LASSO and random forest algorithms, we prioritized the core genes and developed a logistic regression-based diagnostic model. Despite transregional cellular landscape conservation, major cell types varied in abundance. Detailed analysis delineated various excitatory neuron subtypes\u2019 dynamic trajectories, intricate expression, and functional reorganization, with pronounced dysfunction in the posterior hippocampal and temporal cortex networks, indicating hyperactive pro-epileptic effects. Excitatory neurons exhibit an intrinsic ability to autonomously organize themselves into distinct, highly active modules, characterized by a high activation state during epileptogenesis, as illustrated by ten epilepsy-associated functions. Transcription circuits FOSL2\/FOS\/EGR3\/EGR1 promote neuronal hyperexcitability. Integrating epilepsy bulk RNA-seq data, we identified 24 overlapping genes between differential genes and circuit targets. The LASSO and random forest algorithms prioritized three core genes (IL1B, SOCS6, and COL4A1). A logistic regression model based on these three genes showed variable performance, with an apparent AUC of 1.000 in the discovery cohort (GSE256068) and AUCs of 0.974 and 0.722 in and two validation cohorts, indicating the need for further validation. Our study establishes the FOSL2\/FOS\/EGR3\/EGR1 circuit as a master regulator of pathological neuronal hyperactivity across epileptic foci, linking transcriptional activation to network dysfunction. Identifying overactive factors may represent a candidate molecular pathway for future therapeutic exploration against hyperexcitability.<\/jats:p>","DOI":"10.3390\/ijms27104466","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T14:40:31Z","timestamp":1779115231000},"page":"4466","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Uncovering the Key Circuit FOSL2\/FOS\/EGR3\/EGR1, Contributing to the Hyperexcitability of Excitatory Neurons in the Epileptic Temporal Cortex and Hippocampus"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4113-6936","authenticated-orcid":false,"given":"Jing","family":"Chen","sequence":"first","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bowen","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyue","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5263-1635","authenticated-orcid":false,"given":"Wanqi","family":"Mi","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhi","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqi","family":"Jiang","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congxue","family":"Hu","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Intelligent Medicine and Technology (Big Data Research Center), Hainan Medical University, Haikou 571199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3709-3656","authenticated-orcid":false,"given":"Yunpeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"},{"name":"School of Intelligent Medicine and Technology (Big Data Research Center), Hainan Medical University, Haikou 571199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9794-2648","authenticated-orcid":false,"given":"Xia","family":"Li","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1056\/NEJMra022308","article-title":"Epilepsy","volume":"349","author":"Chang","year":"2003","journal-title":"N. 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