Flavonoids in Sepsis: Mechanistic Modulation of Inflammatory Pathways and Therapeutic Potential-A Systematic Review of Preclinical Studies

Yunita Dewani; Gusbakti Rusip; Boyke Marthin Simbolon

doi:10.71197/jsocmed.v5i5.255

Review Articles Open Access CC BY 4.0

Flavonoids in Sepsis: Mechanistic Modulation of Inflammatory Pathways and Therapeutic Potential-A Systematic Review of Preclinical Studies

Yunita Dewani , Gusbakti Rusip , Boyke Marthin Simbolon

First published: 31 May 2026 |https://doi.org/10.71197/jsocmed.v5i5.255

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Abstract

Introduction: Sepsis is a life-threatening syndrome driven by dysregulated host immunity, excessive inflammation, oxidative stress, endothelial injury, and immunosuppression. Flavonoids are bioactive polyphenols with anti-inflammatory and antioxidant effects; however, their therapeutic relevance in sepsis remains primarily preclinical.

Methods: A systematic review was conducted using PubMed/MEDLINE, Scopus, Web of Science, and Embase to identify controlled in vivo studies that evaluated the effects of flavonoids in experimental sepsis or endotoxemia. Eligible studies compared flavonoid-treated animals with septic controls and reported survival, organ injury, inflammatory, oxidative, and mechanistic outcomes. Evidence was qualitatively synthesized, with survival findings contextualized using relevant preclinical meta-analytic data.

Results: Eighty eligible studies were synthesized, predominantly rodent models using lipopolysaccharide-induced endotoxemia or cecal ligation and puncture. More than 30 flavonoids have been reported, including quercetin, kaempferol, luteolin, apigenin, fisetin, and orientin. Flavonoids reduce TNF-α, IL-6, IL-1β, oxidative stress, and organ injury in the pulmonary, renal, hepatic, and cardiovascular systems. Aggregated evidence suggests approximately 50% higher survival in flavonoid-treated animals. The mechanisms included NF-κB and MAPK inhibition, Nrf2/HO-1 activation, endothelial protection, and macrophage polarization. The limitations of this study include the prophylactic designs, heterogeneity, and limited clinical evidence.

Conclusion: Flavonoids exhibit consistent multi-target immunomodulatory and organ-protective effects in experimental sepsis. Translation requires standardized post-insult studies, improved bioavailability, pharmacokinetic evaluation, and early phase clinical trials.

Keywords: Sepsis, Flavonoids, inflammation, Oxidative Stress, NF-kB, Nrf2, MAPK, Macrophage Polarisation, Organ Injury

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INTRODUCTION

Sepsis is defined as life-threatening organ dysfunction caused by dysregulated host response to infection. It remains one of the leading causes of mortality in intensive care units worldwide, accounting for an estimated 11 million deaths annually, with hospital mortality exceeding 40% in septic shock [1-3]. Contemporary understanding recognises sepsis as a complex, time-dependent syndrome characterised not only by excessive inflammation but also by concurrent immunosuppression, endothelial dysfunction, mitochondrial injury, and maladaptive immunometabolic reprogramming [4,5]. This multidimensional pathobiology contributes to marked clinical heterogeneity and inconsistent therapeutic responses.

Despite advances in early recognition, antimicrobial therapy, source control, hemodynamic optimization, and organ support, no sepsis-specific pharmacological intervention has consistently demonstrated survival benefits in large phase III trials. Targeted strategies directed at single mediators, including anti-TNF-α, anti-IL-6, high-dose corticosteroids, and activated protein C, have produced disappointing or context-dependent results [6]. These limitations highlight the need for multi-target therapeutic approaches capable of modulating the interconnected inflammatory, oxidative, endothelial, and metabolic pathways. Flavonoids are structurally diverse plant-derived polyphenolic compounds characterized by a benzo-γ-pyrone core and classified into major subclasses such as flavonols, flavones, flavanones, flavanonols, isoflavones, and anthocyanins. Representative compounds include quercetin, kaempferol, fisetin, luteolin, apigenin, naringenin, pinocembrin, genistein, and orientin [7,8]. Extensive experimental evidence has demonstrated their anti-inflammatory, antioxidant, vasoprotective, endothelial-stabilizing, and immunomodulatory properties across inflammatory and infectious disease models. Mechanistically, flavonoids interact with key signalling pathways central to sepsis pathogenesis, including inhibition of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signalling, activation of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) antioxidant axis, attenuation of inflammasome activation, and modulation of macrophage polarisation [9-12]. Several systematic reviews and meta-analyses have evaluated individual flavonoids or selected flavonoid subclasses in experimental sepsis, and pooled preclinical data suggest a favourable survival signal in treated animals [13-19]. However, existing syntheses remain fragmented, often focusing on single compounds, single mechanisms, or limited outcome domains. A comprehensive class-wide review integrating recent preclinical evidence, organ-specific protective effects, mechanistic convergence, and translational readiness is lacking.

Nevertheless, the translation of flavonoids from experimental sepsis models into clinical practice remains constrained by poor aqueous solubility, limited bioavailability, rapid metabolism, heterogeneous dosing regimens, and frequent reliance on prophylactic rather than therapeutic intervention designs. Furthermore, variability across sepsis models, animal species, timing of administration, formulation strategies, and outcome definitions complicates interpretation and limits the direct extrapolation to human sepsis. Therefore, this systematic review aimed to synthesize contemporary preclinical evidence on flavonoids in experimental sepsis, with an emphasis on in vivo models, survival outcomes, organ protection, and clinically relevant mechanistic pathways. This review also seeks to identify key translational barriers and propose strategic directions for future therapeutic development.

METHOD

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Given the predominance of preclinical evidence, additional methodological considerations specific to animal research were incorporated, including the appropriateness of the sepsis model, intervention timing, route of administration, outcome assessment windows, and clinical relevance of reported endpoints. Eligibility was structured according to the PECO framework. The population comprised mammalian in vivo models of sepsis or endotoxemia. Exposure was defined as the administration of a chemically defined flavonoid compound or a well-characterized flavonoid-rich preparation. The comparator was a septic control group that received a vehicle, placebo, or no flavonoid treatment. The outcomes included survival, organ injury, inflammatory biomarkers, oxidative stress indices, endothelial or vascular dysfunction, and mechanistic endpoints. Studies were eligible if they were controlled in vivo experiments using established models of sepsis, including lipopolysaccharide (LPS)-induced endotoxemia, cecal ligation and puncture (CLP), cecal inoculum, or defined bacterial challenge. Studies were excluded if they were exclusively in vitro, lacked an appropriate septic control group, evaluated uncharacterized multi-component interventions without adequate controls, or were conference abstracts without sufficient extractable data.

A comprehensive literature search was performed in PubMed/MEDLINE, Scopus, Web of Science, and Embase from database inception to March 2026. The search strategy combined terms related to flavonoids, sepsis, inflammatory pathways, organ injury, and animal models using the Boolean operators. No language restrictions were applied. The core search string included combinations of flavonoid, flavonol, flavone, quercetin, kaempferol, luteolin, apigenin, fisetin, naringin, sepsis, septic shock, endotoxemia, cecal ligation and puncture, lipopolysaccharide (LPS), inflammation, NF-κB, cytokine, organ dysfunction, survival, animal, mice, “rat, and murine. Reference lists of relevant reviews and meta-analyses were manually screened. Additional targeted searches were performed to identify recent studies published between 2020 and 2026, formulation and bioavailability studies, and relevant primary studies not captured by the initial database search.

After the removal of duplicates, titles and abstracts were screened against predefined eligibility criteria. Full texts were retrieved for all potentially relevant records and assessed for their final inclusion. Studies identified from systematic reviews, meta-analyses, or reference lists were included if they fulfilled the eligibility criteria and provided sufficient extractable data. Any uncertainty during the screening or eligibility assessment was resolved through discussion and consensus. Data were extracted using a standardized framework. The extracted variables included the year of publication, country, study design, animal species, strain, sex, sample size, sepsis model, method of induction, model severity, and timing of outcome assessment. Intervention-related variables included flavonoid compounds, subclasses, sources or purities, doses, routes of administration, timings relative to sepsis induction, frequencies of administration, and formulation strategies. The outcome variables included survival or mortality, organ injury, inflammatory response, oxidative stress, endothelial or vascular function, and mechanistic readouts. Organ injury outcomes included histopathological findings and biochemical markers, such as serum creatinine, blood urea nitrogen, liver transaminases, and tissue injury scores. The inflammatory mediators included TNF-α, IL-6, IL-1β, HMGB1, and related cytokines. The oxidative stress indices included reactive oxygen species, malondialdehyde, superoxide dismutase, glutathione, and catalase. Safety and toxicity data were extracted when they were available. The risk of bias in animal studies was assessed using the SYRCLE Risk of Bias Tool. The evaluated domains included sequence generation, baseline comparability, allocation concealment, random housing, blinding of investigators and outcome assessors, incomplete outcome data, selective outcome reporting, and other potential sources of bias. Because methodological reporting in preclinical studies is often incomplete, the certainty of the evidence was interpreted conservatively. Greater emphasis was placed on the consistency of the direction of effect across independent studies, biological plausibility of mechanisms, reproducibility across different sepsis models, and concordance between functional outcomes and mechanistic findings.

Given the substantial heterogeneity in flavonoid compounds, doses, routes of administration, treatment timing, sepsis models, animal species, and outcome definitions, a formal de novo meta-analysis was not performed. The findings were synthesized narratively according to major outcome domains, including survival, organ protection, inflammatory modulation, oxidative stress attenuation, endothelial protection, and mechanistic pathways. When multiple studies evaluated the same flavonoid, the results were integrated to identify compound-specific patterns. Quantitative survival effects were contextualized using available preclinical meta-analytic evidence rather than being recalculated. The final synthesis prioritized consistency, biological coherence, translational relevance, and limitations affecting applicability to human sepsis.

RESULTS

A total of 80 studies were included, comprising predominantly preclinical animal experiments, supplemented by a limited number of systematic reviews and meta-analyses. The evidence base was overwhelmingly derived from rodent models, with only a single canine study identified and no large-scale human clinical trials. Across the included studies, more than 30 distinct flavonoids or flavonoid-rich preparations were evaluated. Quercetin emerged as the most extensively investigated compound, followed by kaempferol, fisetin, luteolin, and apigenin, reflecting a concentration of evidence around flavonol and flavone sub-classes. The predominant experimental models were lipopolysaccharide (LPS)-induced endotoxemia and cecal ligation and puncture (CLP), which together accounted for the majority of the study designs. A smaller subset employed live bacterial infection models, including Escherichia coli, CRAB, and MRSA, thereby enhancing translational relevance through the incorporation of pathogen-driven immune responses.

Table 1. summarizes the characteristics of all the included studies.


Study		Study type	Flavonoid(s) tested	Animal model / cell line		Primary organ(s) studied
Qian Ren et al., 2019	No	In vivo	Fisetin [20]	Male C57BL/6J mice [20]	LPS i.p. (10 mg/kg) [20]	Kidney [20]
H. J. Park et al., 2018 F. Koç et al., 2020	Yes No	In vitro + in vivo In vivo	Tamarixetin [21] Chrysin [22]	C57BL/6 and BALB/c mice; BMDCs [21] Rats [22]	LPS and E. coli K1 infection [21] LPS i.p. [22]	Lung, liver, kidney [21] Liver, lung, kidney [22]
A. Chauhan et al., 2019 Yi-Ru Liao & Jin-Yuarn	Yes No	In vivo + in vitro In vivo	Isorhamnetin [15] Quercetin, Quercetin-3-glucuronide	Female BALB/c mice; HEK-Blue hTLR4 cells [15] Mice [23]	E. coli K1 infection [15] LPS i.p. [23]	Lung, liver, kidney [15] Peritoneal cavity [23]
Lin, 2015 W. Cui et al., 2019	Yes	In vivo	[23] Quercetin [24]	Wistar albino rats [24]	CLP [24]	Lung [24]
Haifeng Zhang et al.,	No	In vivo + in vitro	Fisetin [7]	Mice; BMDMs [7]	CLP [7]	Lung, liver, kidney [7]
2020 M. Karamese et al., 2016	No	In vivo	Apigenin [5]	Female Wistar albino rats	CLP [5]	Spleen [5]
Lichao Sun et al., 2017	No	In vivo	Acacetin [25]	(n=64) [5] Mice [25]	Sepsis-induced ALI [25]	Lung [25]
A. Shehata et al., 2024	No	In vivo	Morin [26]	Male mice (n=80) [26]	Not specified [26]	Kidney [26]
Yuanshuo Ouyang et al., 2021	No	In vivo + in vitro	Acacetin [27]	Mice [27]	LPS injection [27]	Liver, lung [27]
Shanting Liao et al.,	No	In vivo	Baicalin [28]	Mice [28]	LPS injection [28]	Liver, kidney [28]
2016 P. Bayram et al., 2023	No	In vivo	Baicalein, Naringin [29]	Wistar albino rats (n=66)	CLP [29]	Not specified [29]
H. Lee et al., 2022	Yes	In vitro + in vivo	Rhamnetin [8]	[29] Female ICR mice; RAW	CRAB and E. coli infection	Lung, liver, kidney [8]
Y. D. Rattmann et al.,	No	In vivo	Myricetin and quercetin rhamnosides	264.7, HEK cells [8] Mice [2]	[8] CLP [2]	Lung, ileum [2]
2012			[2]
Shan Lu et al., 2021	No	In vivo + in vitro	Quercetin (nanoparticle) [18]	Mice; HK-2 cells [18]	LPS [18]	Kidney [18]
Zuqing Xu et al., 2023	No	In vivo	Kaempferol [30]	Mice [30]	CLP [30]	Kidney [30]
Murat Bıçakçıoğlu et al., 2023 M. Doğukan et al., 2021	Yes No	In vivo In vivo	Quercetin (20 mg/kg) [31] Quercetin (20 mg/kg) [32]	Male Sprague Dawley rats (n=32) [31] Male rats (n=32) [32]	CLP [31] Cecal ligation [32]	Lung [31] Liver [32]
Yukun Liu et al., 2021	No	In vivo	Alpinetin (50 mg/kg IV) [33]	Mice [33]	CLP [33]	Multiple organs [33]
Lili Feng et al., 2014	No	In vivo + in vitro	Pentamethoxyflavanone (PMFA) [12]	Mice; M1 macrophages [12]	LPS and CLP [12]	Lung [12]
Xuan Zhu et al., 2022 Gaoxiang Li et al., 2024	No No	In vitro + in vivo In vivo + in vitro	Kaempferol [16] Pinocembrin [34]	Mice; RAW264.7, HUVECs [16] Mice [34]	LPS [16] CLP and LPS [34]	Pulmonary v asculature [16] Vascular (thrombosis)
Yilin Wang et al., 2018	No	In vivo	Mangiferin [35]	Mice (n=24) [35]	CLP [35]	[34] Lung [35]
D. Rabha et al., 2018	No	In vivo	Kaempferol (100 mg/kg oral) [36]	Mice [36]	CLP [36]	Lung [36]
Y. Zong & Huali Zhang, 2017	No	In vivo	Amentoflavone [9]	Rats [9]	CLP [9]	Lung [9]

Table 1. (continued 2)


Study	Full text?	Study type	Flavonoid(s) tested	Animal model / cell line	Sepsis induction	Primary organ(s) studied
Lili Feng et al., 2019	No	In vitro + in vivo	5,7,2',4',5'-Pentamethoxyflavanone	Mice [37]	LPS [37]	Lung [37]
Hong-bo Zhang et al.,	No	In vivo	[37] Astilbin [38]	Rats [38]	CLP [38]	Lung [38]
2017 Yuanfeng Zhu et al.,	No	In vitro + in vivo	Quercetin [11]	Mice; peritoneal	LPS [11]	Lung [11]
2019 S. Rungsung et al., 2022	No	In vivo	Luteolin (0.2 mg/kg IP) [39]	macrophages [11] Mice [39]	CLP [39]	Vascular (aorta) [39]
G. Kim et al., 2023	Yes	In vivo	Procyanidin B2 (0.5–2 mg/kg IV) [40]	Male C57BL/6 mice [40]	LPS i.p. [40]	Lung [40]
Mevlüt Doğukan et al., 2021 Yu-Ge Zhou et al., 2025	Yes No	In vivo In vitro + in vivo	Quercetin (20 mg/kg oral) [41] Quercetin-3-β-aminobutyrate (HPS-β)	Male Sprague Dawley rats (n=32) [41] Mice; RAW264.7 [19]	Cecal ligation [41] LPS [19]	Liver [41] Lung, intestine [19]
Liangyong Deng et al.,	No	In vivo + in vitro	[19] Luteolin [6]	WT and TLR4-deficient	Not specified [6]	Liver [6]
2025 Lichao Sun et al., 2019	No	In vivo	Luteolin (20–80 mg/kg oral) [42]	mice [6] Mice (n=50) [42]	Sepsis-induced ALI [42]	Lung [42]
M. Karamese, 2023	No	In vivo	Naringin [43]	Wistar albino rats (n=30)	CLP [43]	Kidney [43]
Yu-fei Li et al., 2025	No	In vitro + in vivo	Protocatechuic aldehyde [44]	[43] Mice; macrophages [44]	LPS [44]	Not specified [44]
Y. Jafari-khataylou et al.,	No	In vivo	Troxerutin [45]	Mice [45]	LPS [45]	Liver [45]
2020 A. Soltanian et al., 2019	No	In vivo	Quercetin (2 mg/kg IV) [46]	Mixed-breed dogs (n=15)	LPS (0.1 µg/kg IV) [46]	Heart, liver [46]
Zheng Lijun et al., 2025	Yes	In vivo + in vitro	Apigenin (50 mg/kg) [47]	[46] C57BL/6 male mice;	LPS (5 mg/kg) [47]	Intestine [47]
Yanjun Zheng et al.,	No	In vivo + in vitro	Orientin [48]	Caco-2 cells [47] Mice; BMDMs,	LPS [48]	Lung [48]
2026 Haifeng Zhang et al.,	No	In vivo + in vitro	Fisetin (10 mg/kg IP) [49]	RAW264.7 [48] Mice; BMDMs [49]	CLP [49]	Lung, liver, kidney [49]
2020a Jianying Wang et al.,	No	In vivo	Afzelin [50]	Mice [50]	CLP [50]	Kidney [50]
2021 Protective effects of	Yes	In vivo	Quercetin (20 mg/kg oral) [51]	Sprague Dawley rats	Intestinal ligation and	Kidney [51]
quercetin, 2022 Aya Mohamed et al.,	No	In vivo	Morin (50 mg/kg) [3]	(n=31) [51] Mice [3]	puncture [51] LPS (5 mg/kg) [3]	Kidney [3]
2023 Jiafu Li et al., 2025	Yes	In vitro + in vivo	Kakkalide (20 mg/kg IP) [52]	Male C57BL/6J mice	CLP [52]	Lung, kidney [52]
Amira Rifdatari, 2017	No	In vivo	Flavonoid-containing A. paniculata	(n=40); HUVECs [52] Male Wistar rats (n=20)	LPS [53]	Duodenum [53]
Almaz Zaki et al., 2024	No	In vivo + in vitro	extract [53] Vitexin [54]	[53] C57BL/6 mice; MLE-12,	LPS [54]	Lung [54]
Pradipta Reza Syahruna et al., 2020	No	In vivo	Mangosteen peel extract [55]	RAW264.7 [54] Mice (n=30) [55]	Shigella dysenteriae i.p. [55]	Not specified [55]

Table 1. (continued 4)


Study	Full text?	Study type	Flavonoid(s) tested	Animal model / cell line	Sepsis induction	Primary organ(s) studied
N. Aisyah, 2017	No	In vivo	Flavonoid-containing A. paniculata extract [56]	Rats [56]	LPS [56]	Ileum [56]
Edinildo de Oliveira Rodrigues Junior et al., 2023	No	Systematic review + meta-analysis	30 different flavonoids [1]	Various [1]	Various [1]	Multiple [1]
Jiawei Zhou et al., 2018	Yes	Systematic review + meta-analysis	Resveratrol [13]	Various rodents [13]	LPS and CLP [13]	Multiple organs [13]
Yu-Cheng Chang et al., 2013	Yes	In vitro + in vivo	Quercetin [4]	Male C57BL/6J mice; RAW264.7 [4]	LPS i.p. (10 mg/kg) [4]	Systemic [4]
M. Berköz et al., 2021	No	In vivo	Myricetin, Apigenin (100–200 mg/kg oral) [57]	Mice (n=36) [57]	LPS [57]	Liver [57]
Weichao Ding et al., 2024	No	In vitro + network pharmacology	Kaempferol [58]	MH-S cells [58]	LPS [58]	Lung (ARDS) [58]
Xia Cao et al., 2024	No	In vivo + metabolomics	Quercetin, Acacetin, Diosmetin (in YZC extract) [59]	Mice [59]	Not specified [59]	Lung, intestine [59]
Bo-tao Chang et al., 2023	No	In vitro + in vivo	Mangiferin (20 mg/kg) [60]	Mice; RAW264.7 [60]	LPS [60]	Liver, intestine [60]
Liuye Yang et al., 2024	No	In vitro + in vivo	Pimpinellin [61]	C57 and PARP1 knockout mice [61]	LPS [61]	Not specified [61]
Lisa Savitri & Maria Do Carmo Da Costa Freitas, 2024	No	In vivo	Flavonoid-containing P. foetida extract [62]	White male mice (n=24) [62]	E. coli injection [62]	Liver [62]
Rezya Salsabela et al., 2023	Yes	In vivo	Flavonoid-containing A. paniculata extract [63]	Male Wistar rats (n=25) [63]	LPS (5 mg/kgBW) [63]	Systemic (CRP, ferritin) [63]
Naelaturroja Naelaturroja et al., 2020	No	In vivo	Flavonoid-containing I. cylindrica extract [64]	Male DDY mice [64]	LPS [64]	Liver [64]
Hilal Üstündağ et al., 2025	No	In vivo	Propolis-based nanocomposites [65]	Sprague-Dawley rats (n=42) [65]	LPS (5 mg/kg) [65]	Lung [65]
Mutiara Indah Sari et al., 2023	No	In vivo	Flavonoid-containing C. amboinicus extract [66]	Male R. norvegicus (n=28) [66]	Not specified [66]	Liver [66]
Yang (楊斯皓), 2013	No	In vitro + in vivo	Tetramethoxyflavone (TMF) [67]	C57BL/6 mice; RAW264.7 [67]	LPS [67]	Systemic [67]
Diding Heri Prasetyo & E. L. Suparyanti, 2013	Yes	In vivo	Propolis ethanol extract [14]	Male R. norvegicus (n=40) [14]	Cecal inoculum [14]	Intestine [14]
Xiaoxue Bai et al., 2022	No	In vitro + in vivo	Maackiain [10]	Mice; RAW264.7 [10]	CLP and LPS [10]	Multiple organs [10]
Wafiq Azizah et al., 2023	Yes	In vivo	Flavonoid-containing S. album extract [68]	Male mice (n=27) [68]	MRSA injection [68]	Immune cells [68]
A. Esmat et al., 2019	Yes	In vivo	Propolis extract (250 mg/kg oral) [69]	Male albino rats (n=40) [69]	Cecal slurry [69]	Liver, brain [69]
Riswanto Riswanto et al., 2020	No	In vivo	Flavonoid-containing M. oleifera extract [70]	Male Wistar rats (n=30) [70]	LPS [70]	Liver [70]
Jingqian Su et al., 2024	No	In vivo	Turmeric kombucha (flavonoid-containing) [71]	Mice [71]	LPS [71]	Lung [71]

Table 1. (continued 4)

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Issue: Vol. 5 No. 5 (2026): May
Section: Review Articles
Pages: 157-172
Published: 31 May 2026
DOI: https://doi.org/10.71197/jsocmed.v5i5.255
License: CC BY 4.0

How to Cite

Yunita Dewani, Gusbakti Rusip , Boyke Marthin Simbolon (2026). Flavonoids in Sepsis: Mechanistic Modulation of Inflammatory Pathways and Therapeutic Potential-A Systematic Review of Preclinical Studies. Journal of Society Medicine, 5(5), 157-172. https://doi.org/10.71197/jsocmed.v5i5.255

Study	Full text?	Study type	Flavonoid(s) tested	Animal model / cell line	Sepsis induction	Primary organ(s) studied
Kaiyuan Liu et al., 2024	No	In vivo + in vitro	Myricanol [72]	Mice (incl. SIRT1-knockout) [72]	LPS [72]	Lung [72]
Shod Abdurrachman Dzulkarnain et al., 2024	Yes	In vivo	Flavonoid-containing P. betle extract [73]	BALB/c mice [73]	ESBL-producing E. coli [73]	Lung, kidney, liver [73]
Devika Yuldharia, 2012	No	In vivo	Propolis ethanol extract [74]	White male rats (n=40) [74]	Cecal inoculum i.p. [74]	Intestine [74]
Berty, 2010	No	In vivo	Angkak (flavonoid-containing) [75]	Male BALB/c mice (n=24) [75]	Cecal inoculum [75]	Systemic (neutrophils) [75]
Danar Dwi Anandika, 2009	No	In vivo	Garlic extract (flavonoid-containing) [76]	Male BALB/c mice (n=27) [76]	S. aureus infection [76]	Systemic (leukocytes) [76]
Kusni Kurnia Putri, 2012	No	In vivo	Propolis ethanol extract [77]	Male rats (n=40) [77]	Cecal inoculum (40 mg i.p.) [77]	Systemic (lymphocytes) [77]
S. Abdul-Rahman et al., 2026	No	Systematic review	Genistein [17]	Various (10 in vitro, 19 animals, 1 human) [17]	Various [17]

Flavonoids in Sepsis: Mechanistic Modulation of Inflammatory Pathways and Therapeutic Potential-A Systematic Review of Preclinical Studies

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