{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T20:15:33Z","timestamp":1793736933183,"version":"4.6.1"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81501806"],"award-info":[{"award-number":["81501806"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005230","name":"Natural Science Foundation of Chongqing Municipality","doi-asserted-by":"publisher","award":["cstc2018jcyjAX0745, CSTB2023NSCQ-MSX0215"],"award-info":[{"award-number":["cstc2018jcyjAX0745, CSTB2023NSCQ-MSX0215"]}],"id":[{"id":"10.13039\/501100005230","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Enterovirus 71 (EV71) exploits host lipid metabolism and autophagy to establish a cellular environment conducive to viral replication. Although lipoprotein(a) (Lp(a)) has been implicated in metabolic and inflammatory processes, its role and underlying mechanisms in EV71 infection remain poorly understood. This study investigated whether intracellular Lp(a) contributes to EV71 replication and explored the associated signaling mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>RD, HEK293, and Caco-2 cells were infected with EV71 and treated with exogenous Lp(a). Intracellular lipid profiles were analyzed at different stages of infection. EV71 replication was evaluated by VP1 immunoblotting, cytopathic effect assessment, and TCID50 assays. Autophagy was assessed by LC3-II\/LC3-I and p62 immunoblotting and LC3 puncta formation, with pharmacological modulation using chloroquine, 3-methyladenine, and rapamycin. p38 MAPK activation was examined by phosphorylated p38 immunoblotting and pharmacologically inhibited using Nilotinib, PD169316, and Adezmapimod. The expression and functional involvement of Lp(a)-associated receptors, including SR-BI, PLGRKT, LRP1, and LDLR, were assessed by quantitative PCR, immunoblotting, and receptor-specific siRNA knockdown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>EV71 infection selectively increased intracellular Lp(a) levels, whereas other major lipid and apolipoprotein parameters remained largely unchanged. Exogenous Lp(a) enhanced EV71 VP1 expression and viral titers in a dose- and time-dependent manner and promoted viral replication in multiple cell models. Lp(a) markedly enhanced EV71-induced autophagy, characterized by increased LC3-II accumulation and LC3 puncta formation and reduced p62 levels; inhibition of autophagy attenuated the pro-viral effect of Lp(a). Mechanistically, Lp(a) increased p38 MAPK phosphorylation, while pharmacological inhibition of p38 MAPK reduced Lp(a)-induced autophagy and EV71 replication. EV71 infection increased the expression of SR-BI, PLGRKT, LRP1, and LDLR in a time-dependent manner. Knockdown of each receptor reduced intracellular Lp(a) accumulation and significantly decreased EV71 VP1 expression. Furthermore, p38 MAPK inhibition suppressed both transcriptional and protein-level upregulation of these receptors and reduced EV71-induced intracellular Lp(a) accumulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings identify Lp(a) as a previously unrecognized host lipid factor that facilitates EV71 replication through activation of the p38 MAPK-autophagy pathway. The concomitant p38 MAPK-dependent upregulation of Lp(a)-associated receptors may establish a positive feedback loop that enhances intracellular Lp(a) accumulation and sustains a pro-viral cellular state. The Lp(a)-p38 MAPK-autophagy axis and its associated receptors may therefore represent potential targets for antiviral intervention against EV71 infection.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1865808","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T12:15:40Z","timestamp":1785932140000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Lipoprotein (a) fuels EV71 replication by activating p38 MAPK-autophagy axis"],"prefix":"10.3389","volume":"17","author":[{"given":"Lili","family":"Deng","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingbing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, The Second Affiliated 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