{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T05:57:16Z","timestamp":1790575036316,"version":"4.1.0"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"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. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Myeloproliferative neoplasms (MPNs) are driven by constitutive cytokine-receptor signaling, yet the metabolic programs associated with driver genotype and inflammatory remodeling remain incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Here we integrated a 60-case clinical MPN cohort, the GSE174060 Affymetrix Human Transcriptome Array 2.0 microarray dataset, immune deconvolution, exploratory feature prioritization, the GSE228995 mouse single-cell RNA sequencing (scRNA-seq) dataset, human-sample validation, and functional perturbation assays to investigate whether cuproptosis-related metabolism is associated with total calreticulin (CALR) abundance and Janus kinase\u2013signal transducer and activator of transcription (JAK\u2013STAT)-related inflammatory signaling. GSE174060 included 36 samples: 6 essential thrombocythemia (ET), 11 polycythemia vera (PV), 9 primary myelofibrosis (PMF), 4 secondary myelofibrosis (SMF), and 6 healthy control (HC) samples.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Clinically, CALR-mutated cases were enriched for thrombocytosis and distinctive megakaryocytic abnormalities, while inflammatory and fibrotic features tracked with higher interleukin-6 (IL-6), tumor necrosis factor-\u03b1 (TNF-\u03b1), and lactate dehydrogenase (LDH). Microarray-based transcriptomic analyses identified an MPN-associated cuproptosis-related and immune-response program, and consensus clustering separated samples into exploratory transcriptomic clusters. Within this expression-derived partition,\n                      <jats:italic>post hoc<\/jats:italic>\n                      multi-algorithm feature prioritization recurrently retained FDX1 and CALR among genes associated with the Cluster 1-versus-Cluster 2 transcriptional contrast. Single-cell analyses localized Calr and Fdx1 across hematopoietic and immune populations and highlighted inferred JAK\u2013STAT-associated communication potential. In human MPN samples, FDX1 and total CALR protein and mRNA levels were increased and accompanied by STAT5 phosphorylation and elevated inflammatory mediators. Functionally, FDX1 knockdown reduced total CALR abundance, STAT5 phosphorylation, cytokine release, sensitivity to copper-dependent cytotoxicity, and proliferation, whereas FDX1 overexpression showed the reciprocal pattern and was partly counteracted by ruxolitinib.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings support an association between FDX1 perturbation, total CALR abundance, STAT5-associated signaling, and inflammatory output in MPN, but do not establish direct regulation of mutant CALR or mutant CALR\u2013MPL signaling.<\/jats:p>\n                  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