{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T13:12:00Z","timestamp":1788959520724,"version":"build-2803163510"},"reference-count":90,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2026,9,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      Antibiotic resistance threatens the effectiveness of conventional antimicrobial agents, underscoring the need for host-directed therapies that enhance immune defense. Here, we present a cross-species discovery pipeline that couples a\n                      <jats:italic toggle=\"yes\">Caenorhabditis elegans\u2013Staphylococcus aureus<\/jats:italic>\n                      liquid-based infection screen with mammalian mechanistic validation to identify small-molecule immunomodulators. Using six\n                      <jats:italic toggle=\"yes\">C. elegans<\/jats:italic>\n                      innate immunity reporter strains, we identified a known small molecule, SKI-II, as a previously unrecognized host-protective compound that activates the\n                      <jats:italic toggle=\"yes\">C. elegans<\/jats:italic>\n                      SKN-1\/Nrf2 oxidative-stress pathway. In mouse RAW264.7 macrophages, SKI-II binds to the ATPase pocket of VCP (Valosin-Containing Protein), activating the PERK-dependent (Protein kinase R [PKR]-like Endoplasmic Reticulum Kinase) Nrf2 signaling regulation axis that reduces the levels of pathogenic ROS (reactive oxygen species). SKI-II treatment also promotes macrophage M1 polarization and a mitochondrial metabolic shift. This work identifies VCP as a druggable node for host-directed immunomodulation and highlights SKI-II as a prototype small molecule that boosts host tolerance to infection, thereby validating our\n                      <jats:italic toggle=\"yes\">C. elegans<\/jats:italic>\n                      -based screening platform for discovering immunomodulators active in mammalian systems.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Enhancing host immunity is a promising strategy to combat\n                        <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                        infection, particularly multidrug-resistant strains. In this study, we applied a\n                        <jats:italic toggle=\"yes\">C. elegans<\/jats:italic>\n                        liquid-based infection screening model to identify the immunomodulatory compound SKI-II. We demonstrate that SKI-II protects against\n                        <jats:italic toggle=\"yes\">S. aureus<\/jats:italic>\n                        infection in both nematodes and mouse macrophages by regulating host oxidative stress pathways rather than directly targeting the pathogen. We reveal a regulatory circuit in which VCP functions as a central node controlling cellular ROS responses and activating the downstream PERK-dependent Nrf2 antioxidant signaling pathway. These findings advance our understanding of host cellular responses to bacterial infection and highlight VCP as a druggable target for host-directed therapeutic strategies against infectious diseases.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.01558-26","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T13:01:06Z","timestamp":1786366866000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Identification of SKI-II as a host-protective immunomodulator against\n                    <i>Staphylococcus aureus<\/i>\n                    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