{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T11:06:48Z","timestamp":1790593608091,"version":"4.1.0"},"reference-count":86,"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. Med."],"abstract":"<jats:p>\n                    Community-acquired pneumonia (CAP) still causes high mortality despite effective antibiotics. Much of this death is driven by a dysregulated host immune response rather than by the pathogen itself, and antimicrobial resistance deepens the problem. Host-directed therapy has accordingly shifted toward precision immunomodulation, yet its benefit appears conditional on the inflammatory state. Stratification by a single inflammator\n                    <jats:italic>y<\/jats:italic>\n                    axis such as C-reactive protein (CRP) separates broad prognostic subgroups, but it does not indicate which effector pathway to target or which agent to use; we designate this limitation, as a conceptual shorthand rather than a validated threshold, the \u201cCRP ceiling.\u201d Existing reviews treat natural-product host-directed therapy, CAP inflammatory endotyping, and human lung organoid modeling separately; the gap we address is the absence of a framework that connects them. Integrating these three fields, we propose, as a hypothesis-generating rather than a validated scheme, an endotype\u2013target\u2013natural-product framework for bacterial CAP. We first outline the interventable core of CAP immunopathology across the inflammasome, neutrophil extracellular trap (NET), and resolution axes, together with the pathogen-specific virulence that biases them; we then propose that the multi-target pharmacology of natural products may suit candidate endotypes driven by several co-activated nodes, where single-target agents have often failed, while noting that their comparatively favorable toxicity is itself a hypothesis rather than an established class property; and we position human lung organoids as a promising human-relevant platform, alongside complementary systems, that could test endotype-, compound-, and pathogen-specific hypotheses and provide a roadmap for validation before clinical translation. The framework is intended to complement, not replace, pathogen-directed treatment, and to reframe host-directed therapy from uniform anti-inflammation toward modulation matched to mechanism, pathogen, and patient. The principal challenges concern immune-competent organoids, validated pathway-level endotype biomarkers, and standardized characterization of multi-component natural products.\n                  <\/jats:p>","DOI":"10.3389\/fmed.2026.1941520","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T10:53:24Z","timestamp":1790592804000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Toward precision host-directed immunomodulation in community-acquired pneumonia: a proposed endotype\u2013target\u2013natural-product framework and a roadmap for validation in human lung organoids"],"prefix":"10.3389","volume":"13","author":[{"given":"Qing","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Pulmonary Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine","place":["Shanghai, 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Pulmonary Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guihua","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Diseases, Shuguang Hospital, Shanghai Institute of Infectious Diseases and Biosecurity, Shanghai University of Traditional Chinese 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