{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T18:08:42Z","timestamp":1776881322808,"version":"3.51.2"},"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Science and Technology Program of the Joint Fund of Scientific Research for the Public Hospitals of Inner Mongolia Academy of Medical Sciences","award":["Grant No. 2024GLLH0862"],"award-info":[{"award-number":["Grant No. 2024GLLH0862"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Secretory phosphoprotein 1 (SPP1) has been linked to tumor progression and immune regulation, but its prognostic value, impact on the tumor immune microenvironment (TIME), and drug sensitivity in HCC remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed a pan-cancer analysis using TIMER and validated SPP1 upregulation in six GEO datasets (GSE45436, GSE54236, GSE121248, GSE76427, GSE64041, and GSE60502) and HPA protein data. In TCGA-LIHC, we assessed overall survival (OS) and progression-free survival (PFS) using univariate\/multivariate Cox analyses, ROC analysis, and a calibrated nomogram. We identified differentially expressed genes (DEGs) and performed GO\/KEGG and GSEA analyses. Immune infiltration was estimated with CIBERSORT and TIMER, and relationships with immune checkpoints were explored. Drug sensitivity was predicted with pRRophetic using GDSC data.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , SPP1 was knocked down or overexpressed in HCC cell lines to evaluate effects on proliferation, migration, invasion, and apoptosis via qRT-PCR, Western blot, CCK-8, colony formation, wound healing, Transwell invasion, and TUNEL assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>SPP1 was significantly upregulated in HCC at mRNA and protein levels. High SPP1 predicted poorer OS and PFS and was associated with higher histological grade, advanced stage, and greater T stage. The nomogram showed good calibration and discrimination. DEGs and enrichment analyses implicated cytokine receptor interaction, fatty acid metabolism, and PI3K-Akt signaling; GSEA confirmed immune- and metabolism-related pathways. High SPP1 correlated with higher immune\/ESTIMATE scores, increased M0\/M2 macrophages and dendritic cells, reduced CD8\u2009+\u2009T cells, and upregulation of multiple immune checkpoints. Drug-sensitivity predictions showed high-SPP1 tumors were more sensitive to several anti-cancer drugs (e.g., sorafenib), while resistance to others was suggested. Functionally, SPP1 knockdown inhibited, while overexpression promoted, proliferation, migration, and invasion; knockdown increased apoptosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>SPP1 acts as an oncogenic driver in HCC, associated with poor prognosis, an immunosuppressive TIME, and distinct drug-response patterns.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0347842","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T17:33:12Z","timestamp":1776879192000},"page":"e0347842","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["The role of SPP1 in evaluating the prognosis, immune infiltration, and drug sensitivity of hepatocellular 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