--- title: "AB-free kava kavalactones suppress cigarette smoke–induced lung inflammation via PKA/CREB/COX-2 si" id: "biorxiv-23-ab-free-kava-and-its-kavalactones-suppress-cigarette-smoke-and" canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-23-ab-free-kava-and-its-kavalactones-suppress-cigarette-smoke-and" content_type: "clinical_feed_article" specialty: "Pulmonology" source_name: "bioRxiv (Biomedical Preprints)" source_url: "https://www.biorxiv.org/content/10.64898/2026.08.21.746215v1?rss=1" published_at: "2026-08-25T12:00:00.000Z" evidence_level: "Verified Feed" license: "CC-BY-NC-4.0 / Informational Use" --- # AB-free kava kavalactones suppress cigarette smoke–induced lung inflammation via PKA/CREB/COX-2 si ## Provenance & Clinical Metadata - **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-23-ab-free-kava-and-its-kavalactones-suppress-cigarette-smoke-and - **Specialty:** [Pulmonology](https://medichelpline.com/clinical-feed/pulmonology.md) - **Primary Source:** bioRxiv (Biomedical Preprints) - **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.08.21.746215v1?rss=1) - **Published At:** 2026-08-25T12:00:00.000Z - **Evidence Rating:** Verified Feed ## Executive GIST (TL;DR) - Cigarette smoke–induced lung inflammation drives pulmonary disease and current anti-inflammatory agents have limited efficacy, motivating search for structurally distinct therapeutics. - An **AB-free kava** formulation (Piper methysticum; depleted of flavokavains A/B) containing six major **kavalactones** previously suppressed smoke-induced lung inflammation in mice. - This study sought to identify bioactive kavalactone(s) and mechanisms using in vitro macrophage assays, cigarette smoke condensate models, and mouse exposures to cigarette smoke or lipopolysaccharide (LPS). - A clear structure–activity relationship emerged for suppression of LPS-stimulated **PGE2** production in macrophages: **desmethoxyyangonin (DMY)** was the most potent, while **dihydrokavain (DHK)** showed minimal activity. - DMY reduced LPS-induced **IL-6** and **TNF-α** production; DHK did not. DMY attenuated **COX-2** induction and lowered phosphorylation of **CREB**, whereas DHK lacked these effects. - Pharmacological inhibition of **protein kinase A (PKA)** similarly reduced p-CREB, COX-2 and PGE2, supporting a **PKA-dependent CREB/COX-2** signaling axis mediating PGE2 suppression. These effects were reported to be independent of **NF-κB** and **AP-1** signaling. - DMY and DHK produced similar relative effects against cigarette smoke condensate–induced proinflammatory pathways and PGE2 in vitro, and in vivo DMY suppressed cigarette smoke–induced lung inflammation while DHK did not. - **Dihydromethysticin (DHM)** showed the greatest in vivo anti-inflammatory efficacy despite only moderate in vitro potency, a discrepancy attributed by the authors to superior bioavailability of DHM relative to DMY. - Cigarette smoke exposure increased p-CREB and COX-2 in mouse lungs; these increases were attenuated by AB-free kava and its bioactive kavalactones with the degree of suppression correlating with in vivo anti-inflammatory efficacy. - DHM also suppressed LPS-induced neutrophil accumulation in mouse lungs. - The authors conclude that bioactive kavalactones in AB-free kava suppress cigarette smoke– and LPS-induced lung inflammation through modulation of the **PKA/CREB/COX-2** axis, supporting further development of structurally distinct anti-inflammatory agents targeting smoke-induced pulmonary inflammation. - Competing interest: the AB-free kava product evaluated is based on IP owned by Kuality Herbceutics; one author holds 75% ownership in that company. Funding reported from the Florida Department of Health. Details such as specific doses, exposure regimens, and full experimental parameters were not reported in the provided abstract. ## Clinical Analysis & Structured Key Points Cigarette smoke-induced lung inflammation is a central driver of pulmonary diseases. The limited efficacy of current anti-inflammatory agents underscores the need for structurally novel therapeutics with distinct mechanisms. We recently demonstrated that AB-free kava, a flavokavains A/B-depleted formulation from Piper methysticum containing six major kavalactones, effectively suppresses cigarette smoke-induced lung inflammation in mice. This study aims to identify the bioactive constituent(s) and elucidate underlying mechanisms. These kavalactones revealed a clear structure-activity relationship in suppressing lipopolysaccharide (LPS)-stimulated prostaglandin E2 (PGE2) production in macrophages with desmethoxyyangonin (DMY) as the most potent kavalactone whereas dihydrokavain (DHK, a structurally similar analog) with minimal activity. DMY also effectively reduced LPS-induced interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-) production while DHK was ineffective. Mechanistically, DMY, but not DHK, attenuated COX-2 induction and reduced phosphorylation of cAMP response element-binding protein (CREB). Pharmacological inhibition of protein kinase A (PKA) similarly reduced p-CREB, COX-2 and PGE2, supporting a PKA-dependent CREB/COX-2 signaling in mediating PGE2 suppression while these effects were independent of nuclear factor kappa B (NF-{kappa}B) and activator protein 1 (AP-1) signaling. Similar results were observed for DMY and DHK in attenuating cigarette smoke condensate-induced proinflammatory pathways and PGE2 production. Consistently, DMY demonstrated significant in vivo efficacy in suppressing cigarette smoke-induced lung inflammation while DHK was not effective. Interestingly, dihydromethysticin (DHM) demonstrated the greatest in vivo anti-inflammatory efficacy, although it only exhibited moderate in vitro potency, likely due to its superior bioavailability over DMY. Concordantly, cigarette smoke exposure elevated p-CREB and COX-2 expressions in mouse lungs, which were attenuated by AB-free kava and its bioactive kavalactones with the extent of suppression correlating with their in vivo anti-inflammatory efficacy. DHM effectively suppressed LPS-induced neutrophil accumulation in mouse lungs as well. Collectively, these studies identify bioactive kavalactones in AB-free kava that suppress cigarette smoke- and LPS-induced lung inflammation through the modulation of the PKA/CREB/COX-2 signaling axis, providing a foundation for developing structurally distinct anti-inflammatory agents, particularly targeting smoke-induced inflammation and associated pulmonary diseases. ## Related Clinical Research - [Triglyceride-Glucose (TyG) Index and Mortality in Non-Diabetic Fibrotic Lung Disease on Antifibrot](https://medichelpline.com/clinical-feed/plos-one-1-association-between-triglyceride-glucose-index-and-all-cause-mortality-in-non.md) - [Pemafibrate as a senotherapeutic for COPD via TFEB-driven autophagy and mitophagy regulation](https://medichelpline.com/clinical-feed/medrxiv-4-senotherapeutic-role-of-pemafibrate-through-autophagy-mitophagy-regulation-in.md) - [Impact of elexacaftor-tezacaftor-ivacaftor on lung function trajectories in children with cystic f](https://medichelpline.com/clinical-feed/medrxiv-10-lung-function-trajectories-in-children-with-cystic-fibrosis-aged-3-17-years.md) - [Connexin 43 in Hyperoxia-Induced Bronchopulmonary Dysplasia and Associated Pulmonary Hypertension](https://medichelpline.com/clinical-feed/plos-one-19-role-of-connexin-43-in-hyperoxia-induced-bronchopulmonary-dysplasia-and.md) - [Determinants of Quality of Life in Pulmonary Tuberculosis: Protocol for a Systematic Review and Me](https://medichelpline.com/clinical-feed/bmj-open-5-factors-influencing-quality-of-life-in-patients-with-pulmonary-tuberculosis-a.md) ## Navigation - [← Back to Pulmonology Feed](https://medichelpline.com/clinical-feed/pulmonology.md) - [← All Clinical Specialties](https://medichelpline.com/clinical-feed.md) ## Medical & Regulatory Disclaimer > [!CAUTION] > MedicHelpline content is structured for research, educational, and professional discovery purposes. 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