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Natural products as multi‑target therapies for sepsis‑induced myocardial dysfunction (Review)

  • Authors:
    • Fei Tang
    • Dong Liu
    • Shi-Chao Zhu
    • Hui-Min Zhou
    • Xue-Wen Qiu
  • View Affiliations / Copyright

    Affiliations: Department of Pharmacy, Chongqing General Hospital, Chongqing University, Chongqing 400014, P.R. China, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, P.R. China
    Copyright: © Tang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 71
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    Published online on: January 22, 2026
       https://doi.org/10.3892/ijmm.2026.5742
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Abstract

Sepsis, an infection‑triggered systemic inflammatory response syndrome, ranks as the third leading cause of death worldwide due to its high incidence and mortality. Sepsis‑induced myocardial dysfunction (SIMD) is a frequent and serious complication that notably increases patient morbidity and mortality. The underlying pathophysiology of SIMD involves a complex interplay of inflammation, oxidative stress, mitochondrial impairment and apoptosis, yet no effective therapies have been established. Thus, uncovering the molecular mechanisms of SIMD, identifying novel therapeutic targets and developing efficacious agents are key. For centuries, natural products have been used in traditional medical systems across China and Asia to manage cardiovascular disease. These compounds can confer cardioprotection by modulating inflammatory pathways, decreasing oxidative stress, inhibiting apoptotic cell death and improving mitochondrial function. The present review aimed to summarize the clinical manifestations and pathophysiology of SIMD and how natural products exert their protective effects. The present study aimed to explore structure‑activity relationships and highlight key molecular targets and representative natural product binding affinities for SIMD‑related proteins. In summary, the present study presents a comprehensive overview of the multi‑targeted strategies employed by natural products against SIMD and provides guidance for the discovery of SIMD‑focused dietary supplements and lead compounds, laying the groundwork for future translational research.

View Figures

Figure 1

Pathophysiological mechanisms of
SIMD. This schematic illustrates the key interrelated pathways
(such as PI3K/Akt, NLRP3 and NF-κB) contributing to SIMD, including
dysregulated cytokine release, oxidative stress, mitochondrial
damage, impaired calcium handling and the regulatory roles of
specific. miRs. SIMD, sepsis-induced myocardial dysfunction; miR,
microRNA HMGB, high mobility group box; TLRS, Toll like receptors;
ROS, reactive oxygen species; SOD, superoxide dismutase; MDA,
malondialdehyde; iNOS, inducible nitric oxide synthase; RNS,
reactive nitrogen species; DRP, dynamin-related protein; PPAR,
peroxisome proliferator activated-receptors; mPTP, mitochondrial
permeability transition pore.

Figure 2

Regulation of programmed cell death
by natural products in SIMD. Natural products attenuate SIMD
through suppression of pro-oxidant NF-κB/TLR signaling, modulation
of PI3K/Akt, AMPK/autophagy, TFEB, NLRP3/pyroptosis and mitophagy
pathways and restoration of GPX4-associated antioxidant defenses.
SIMD, sepsis-induced myocardial dysfunction; TLR, Toll like
receptor; TFEB, T cell transcription factor EB; GPX, Glutathione
peroxidase; SphK, Sphingosine kinases; S1P, Sphingosine Kinase 1;
ROS, reactive oxygen species; MFN, mitofusin; SIRT, sirtuin 1;
GSDMD, gasdermin D; ALOX, arachidonate 5-lipoxygenase.

Figure 3

Anti-inflammatory mechanisms of
natural products in sepsis-induced myocardial dysfunction). Natural
products confer protection by inhibiting pro-inflammatory
TLR4/NF-κB and MAPK signaling cascades, activating the PI3K/Akt
survival pathway, modulating specific miR networks (miR-214-5p,
miR-21) and promoting the polarization of macrophages towards the
reparative M2 phenotype. TLR, toll-like receptor; miR, miRNA; GSK,
glycogen synthase kinase; HO, heme oxygenase; SIRT, sirtuin 1; COX,
cyclooxygenase; iNOS, inducible nitric oxide synthase; IGF, insulin
like growth factor; LDH, lactate dehydrogenase; MCP, monocyte
chemotactic protein; MDA, malondialdehyde; HMGB, high mobility
group box.

Figure 4

Modulation of oxidative stress by
natural products in sepsis-induced myocardial dysfunction). Natural
products primarily enhance antioxidant defenses by activating
enzymes such as SOD, CAT and GSH-Px or by stimulating the Nrf2/HO-1
pathway. They also dampen proinflammatory signaling via NF-κB, TLR4
and ERK1/2-p38 MAPK signaling to reduce NOX2/iNOS-mediated ROS/RNS
production. SOD, superoxide dismutase; CAT, catalase; GSH-Px,
glutathione peroxidase; HO, heme oxygenase; TLR, Toll like
receptor; NOX, nitrogen oxide; iNOS, inducible nitric oxide
synthase; ROS, reactive oxygen species; RNS, reactive nitrogen
species; GSSG, glutathione oxidized; MDA, malondialdehyde; LDH,
lactate dehydrogenase; TAK, transforming growth factor-β-activated
kinase 1.

Figure 5

Targeting mitochondrial dysfunction
with natural products in SIMD. Natural products counteract SIMD by
engaging multiple mitochondrial-protective pathways, most notably
SIRT1/Nrf2, PI3K/Akt/mTOR and AMPK, and by promoting mitochondrial
biogenesis via PGC-1α/TFAM and UPRmt. SIMD, sepsis-induced
myocardial dysfunction; SIRT, sirtuin 1; PGC, peroxisome
proliferator-activated receptor γ coactivator; UPRmt, mitochondrial
unfolded protein response; GSK, glycogen synthase kinase; PTP1B,
protein tyrosine phosphatase 1B; ROS, reactive oxygen species; SOD,
superoxide dismutase; DRP, dynamin-related protein 1; STIM, stromal
interaction molecule 1; CRAC, calcium release-activated
channels.

Figure 6

Classification and structure-activity
analysis of natural products active against sepsis-induced
myocardial dysfunction). (A) Active natural products are mainly
divided into flavonoids, glycosides, phenolic acids, alkaloids and
saponins, lignin and olefins. (B) Pharmacological activity analysis
of natural products shows that functional groups are associated
their antioxidant, anti-inflammatory and cell protective
activities.

Figure 7

Notable therapeutic targets and
network pharmacology analysis in SIMD. (A) Primary actions of
natural products are categorized into anti-inflammatory,
antioxidant, anti-cell death and mitochondrial protection. Major
targeted signaling cascades include NF-κB, MAPK family, TLR4/MyD88,
PI3K/Akt/mTOR, Nrf2/HO-1 and the NLRP3 inflammasome. (B) Network
pharmacology comparison highlights high-frequency SIMD-associated
targets, such as iNOS (NOS2), NF-κB, MAPK members (JNK, ERK1/2),
PI3K/Akt/mTOR, NLRP3, SIRT1 and STAT3. SIMD, sepsis-induced
myocardial dysfunction; TLR, Toll like receptor; HO, heme
oxygenase; iNOS, inducible nitric oxide synthase ; SIRT, sirtuin
1.

Figure 8

Docking of natural products to novel
sepsis-induced myocardial dysfunction) targets. All five compounds
bound tightly to both MMP9 and protein kinase C) (<-8.0
kcal/mol). Baicalein and curcumin also demonstrated appreciable
affinity for cAMP (<-5.0 kcal/mol).
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Copy and paste a formatted citation
Spandidos Publications style
Tang F, Liu D, Zhu S, Zhou H and Qiu X: <p>Natural products as multi‑target therapies for sepsis‑induced myocardial dysfunction (Review)</p>. Int J Mol Med 57: 71, 2026.
APA
Tang, F., Liu, D., Zhu, S., Zhou, H., & Qiu, X. (2026). <p>Natural products as multi‑target therapies for sepsis‑induced myocardial dysfunction (Review)</p>. International Journal of Molecular Medicine, 57, 71. https://doi.org/10.3892/ijmm.2026.5742
MLA
Tang, F., Liu, D., Zhu, S., Zhou, H., Qiu, X."<p>Natural products as multi‑target therapies for sepsis‑induced myocardial dysfunction (Review)</p>". International Journal of Molecular Medicine 57.3 (2026): 71.
Chicago
Tang, F., Liu, D., Zhu, S., Zhou, H., Qiu, X."<p>Natural products as multi‑target therapies for sepsis‑induced myocardial dysfunction (Review)</p>". International Journal of Molecular Medicine 57, no. 3 (2026): 71. https://doi.org/10.3892/ijmm.2026.5742
Copy and paste a formatted citation
x
Spandidos Publications style
Tang F, Liu D, Zhu S, Zhou H and Qiu X: <p>Natural products as multi‑target therapies for sepsis‑induced myocardial dysfunction (Review)</p>. Int J Mol Med 57: 71, 2026.
APA
Tang, F., Liu, D., Zhu, S., Zhou, H., & Qiu, X. (2026). <p>Natural products as multi‑target therapies for sepsis‑induced myocardial dysfunction (Review)</p>. International Journal of Molecular Medicine, 57, 71. https://doi.org/10.3892/ijmm.2026.5742
MLA
Tang, F., Liu, D., Zhu, S., Zhou, H., Qiu, X."<p>Natural products as multi‑target therapies for sepsis‑induced myocardial dysfunction (Review)</p>". International Journal of Molecular Medicine 57.3 (2026): 71.
Chicago
Tang, F., Liu, D., Zhu, S., Zhou, H., Qiu, X."<p>Natural products as multi‑target therapies for sepsis‑induced myocardial dysfunction (Review)</p>". International Journal of Molecular Medicine 57, no. 3 (2026): 71. https://doi.org/10.3892/ijmm.2026.5742
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