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Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>High-linear energy transfer (LET) radiation such as carbon ions exhibits greater biological effectiveness than conventional low-LET X-rays, but the transcriptional mechanisms underlying this advantage remain incompletely understood. We hypothesized that high-LET radiation induces a qualitatively different transcriptional response rather than simply amplifying low-LET signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A549 non-small cell lung cancer cells were exposed to equal physical doses (8 Gy) of X-rays or carbon ions (LET 73 keV\/\u00b5m), and transcriptomic profiling was performed 4\u00a0h post-irradiation. Differential expression analysis was integrated with Hallmark pathway enrichment using gene set enrichment analysis (GSEA), over-representation analysis (ORA), and leading-edge gene interrogation to identify shared and LET-dependent gene expression regulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Both radiation modalities activated a conserved DNA damage response characterized by p53 signaling and apoptosis-related genes. In contrast, carbon ions selectively suppressed mitotic regulators including CENPE, KIF2C, PLK1, and BUB1, consistent with transcriptional disruption of the replication\u2013segregation machinery. High-LET irradiation additionally enriched inflammatory and stress-associated pathways, including tumor necrosis factor (TNF), Nuclear Factor \u03baB (NF-\u03baB) and extracellular matrix and adhesion-related signatures annotated within the Hallmark epithelial\u2013mesenchymal transition (EMT) gene set. Carbon ions also downregulated multiple core and linker histone genes, revealing a chromatin regulatory reprogramming signature although this may reflect modulation of mRNA stability linked to replication stress and cell-cycle progression. KRAS-associated gene networks were enriched under high-LET conditions, reflecting convergence of stress-responsive signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>At equal physical doses, high-LET carbon ion irradiation is associated with a transcriptional program distinct from that of low-LET X-rays, characterized by downregulation of mitotic and chromatin regulatory programs and selective engagement of stress-associated signaling networks. These findings provide mechanistic insight into LET-dependent radiobiology and suggest transcriptional pathway remodeling may contribute to the enhanced biological effectiveness of carbon ions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1869974","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T09:35:27Z","timestamp":1784021727000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcriptomic differences in chromatin and cell cycle regulation in A549 cells after irradiation with carbon ions and X-rays"],"prefix":"10.3389","volume":"16","author":[{"given":"Hasan","family":"Nisar","sequence":"first","affiliation":[{"name":"Department of Radiation Biology, Institute of Aerospace Medicine, German Aerospace Center (DLR)","place":["Cologne, Germany"]},{"name":"Department of Medical Sciences, Pakistan Institute of Engineering and Applied Sciences 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