{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T07:02:26Z","timestamp":1780038146434,"version":"3.53.1"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Introduction<\/jats:title>\n SARS-CoV-2 portrays a public health threat because severe progression of infections can lead to hospitalization. Severity is often characterized by a systemic inflammatory response in later stages, along with disbalance in cytokine production, multi-organ failure, or acute respiratory distress syndrome (ARDS). As severe infections can be challenging due to limited treatment windows for direct-acting antivirals, host-targets, e.g., the Raf\/MEK\/ERK signaling cascade, came into focus. Specifically, MEK1\/2 has been suggested as a target for antiviral and anti-inflammatory therapy. A recent phase II clinical trial showed the efficacy of the MEK1\/2 inhibitor zapnometinib (ZMN\/ATR-002) in hospitalized COVID-19 patients. The anti-inflammatory action of ATR-002 was only studied on some candidate cytokines.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n To generate a comprehensive overview of transcriptional effects on immune regulatory genes, we performed a transcriptome analysis of SARS-CoV-2-infected Calu-3 cells in the presence or absence of ATR-002.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Gene expression data revealed significant upregulation of innate immune-response-related genes, e.g., cytokines (\n CXCL10<\/jats:italic>\n and\n CCL5<\/jats:italic>\n ), which are associated with severe cases of COVID-19, or ISGs (\n MX1<\/jats:italic>\n and\n OASL<\/jats:italic>\n ) induced by the infection. ATR-002 could reverse this effect in the infection. To exclude the possibility that regulated immune-response-related genes are not affected by the reduced viral load upon inhibitor treatment, but by the pathway interference itself, MEK1\/2 inhibition in a non-infectious scenario was tested. Lowered immune regulatory gene expression was traced back to impaired viral replication, as shown by different genes affected in the non-infected contrast. However, some target genes (EGR1, IFNL1, and NLRP1), which could be connected to transcriptional regulation via the Raf\/MEK\/ERK axis, proved to be involved in the modulation of innate immunity. Especially NLRP1 expression was newly identified as a target of MEK1\/2 inhibition, which links Raf\/MEK\/ERK signaling to caspase-1 activity and the subsequent processing of IL-1\u03b2, a major driver of hyperinflammation. MEK1\/2-inhibition-mediated regulation of other targets, such as EGR1, may exert additional immune regulatory processes, influencing inflammation in SARS-CoV-2 infections.\n <\/jats:p>\n <\/jats:sec>\n \n Discussion<\/jats:title>\n With our analysis of transcriptional regulation after SARS-CoV-2 infection and the potential influence of ATR-002, we were able to identify ERK1\/2-dependent gene expression and candidate genes (EGR1, IFNL1, and NLRP1), which could be involved in the regulation of innate immune-response-related processes.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1724353","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T06:10:23Z","timestamp":1780035023000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["MEK1\/2 inhibitor ATR-002 reshapes host transcriptome and modulates immune regulatory genes in SARS-CoV-2 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