{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T05:08:23Z","timestamp":1778562503066,"version":"3.51.4"},"reference-count":48,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T00:00:00Z","timestamp":1776988800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF) grant funded by the Korea government","award":["NRF-RS-2025-00555195"],"award-info":[{"award-number":["NRF-RS-2025-00555195"]}]},{"name":"a grant of the Korea Health Technology R&amp;D Project through the Korea Health Industry Devel-opment Institute (KHIDI), funded by the Ministry of Health &amp; Welfare, Republic of Korea","award":["RS-2025-25410994"],"award-info":[{"award-number":["RS-2025-25410994"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background\/Objectives: Plant-derived phytochemicals are being increasingly explored for their ability to treat various illnesses, especially those affecting the vasculature. High mobility group box 1 (HMGB1) acts as a crucial mediator during the late phase of sepsis, promoting the secretion of pro-inflammatory cytokines and thereby fueling inflammation and systemic complications. Higher plasma HMGB1 levels not only hinder accurate diagnosis and prognosis but also worsen disease outcomes in inflammatory states. Picropodophyllotoxin (PPT), a key bioactive ingredient isolated from the root of Podophyllum hexandrum, has shown a range of beneficial effects, including anti-cancer and anti-proliferative actions, across several tumor types. Nevertheless, its possible involvement in HMGB1-driven severe vascular inflammation remains unexplored. The current work aimed to investigate whether PPT could influence lipopolysaccharide (LPS)-induced HMGB1 activity and its related inflammatory signaling in human umbilical vein endothelial cells (HUVECs). Methods: A combination of in vitro and in vivo approaches was used to assess the anti-inflammatory action of PPT. These included measurements of endothelial barrier function, cell survival, leukocyte attachment and migration, levels of cell adhesion molecules, and the release of pro-inflammatory factors. Both cultured human endothelial cells and mouse disease models were used to thoroughly evaluate how PPT affects HMGB1-triggered inflammatory reactions. Results: The findings showed that PPT markedly reduced HMGB1 movement from inside HUVECs to the outside, thereby limiting its release into the environment. Moreover, PPT effectively decreased neutrophil sticking and migration, lowered the appearance of HMGB1 receptors, and prevented the activation of nuclear factor-\u03baB (NF-\u03baB), a master switch in inflammatory signaling. At the same time, PPT treatment strongly lowered tumor necrosis factor-\u03b1 (TNF-\u03b1) production, adding to its anti-inflammatory profile. Conclusions: Taken together, these results indicate that PPT potently inhibits HMGB1-driven inflammatory processes by acting at several levels of the inflammatory cascade, such as HMGB1 movement, receptor binding, NF-\u03baB activation, and subsequent cytokine release. Therefore, PPT stands out as a hopeful therapeutic option for HMGB1-related inflammatory diseases and deserves further exploration in preclinical and clinical studies.<\/jats:p>","DOI":"10.3390\/biom16050638","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T17:26:18Z","timestamp":1777051578000},"page":"638","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Picropodophyllotoxin Mitigates Severe Inflammation Through HMGB1 Inhibition"],"prefix":"10.3390","volume":"16","author":[{"given":"Gyuri","family":"Han","sequence":"first","affiliation":[{"name":"Research Institute of Pharmaceutical Sciences, Cellular & Molecular Research Institute (CMRI), College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ga Eun","family":"Kim","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmaceutical Sciences, Cellular & Molecular Research Institute (CMRI), College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5756-9367","authenticated-orcid":false,"given":"Jong-Sup","family":"Bae","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmaceutical Sciences, Cellular & Molecular Research Institute (CMRI), College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s12276-022-00736-w","article-title":"The mechanism of hmgb1 secretion and release","volume":"54","author":"Chen","year":"2022","journal-title":"Exp. 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