A detailed overview of quercetin: implications for cell death and liver fibrosis mechanisms

Abstract

Background: Quercetin, a widespread polyphenolic flavonoid, is known for its extensive health benefits and is commonly found in the plant kingdom. The natural occurrence and extraction methods of quercetin are crucial due to its bioactive potential.

Purpose: This review aims to comprehensively cover the natural sources of quercetin, its extraction methods, bioavailability, pharmacokinetics, and its role in various cell death pathways and liver fibrosis.

Methods: A comprehensive literature search was performed across several electronic databases, including PubMed, Embase, CNKI, Wanfang database, and ClinicalTrials.gov, up to 10 February 2024. The search terms employed were "quercetin", "natural sources of quercetin", "quercetin extraction methods", "bioavailability of quercetin", "pharmacokinetics of quercetin", "cell death pathways", "apoptosis", "autophagy", "pyroptosis", "necroptosis", "ferroptosis", "cuproptosis", "liver fibrosis", and "hepatic stellate cells". These keywords were interconnected using AND/OR as necessary. The search focused on studies that detailed the bioavailability and pharmacokinetics of quercetin, its role in different cell death pathways, and its effects on liver fibrosis.

Results: This review details quercetin's involvement in various cell death pathways, including apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, and cuproptosis, with particular attention to its regulatory influence on apoptosis and autophagy. It dissects the mechanisms through which quercetin affects these pathways across different cell types and dosages. Moreover, the paper delves into quercetin's effects on liver fibrosis, its interactions with hepatic stellate cells, and its modulation of pertinent signaling cascades. Additionally, it articulates from a physical organic chemistry standpoint the uniqueness of quercetin's structure and its potential for specific actions in the liver.

Conclusion: The paper provides a detailed analysis of quercetin, suggesting its significant role in modulating cell death mechanisms and mitigating liver fibrosis, underscoring its therapeutic potential.

Keywords: apoptosis; autophagy; cuproptosis; ferroptosis; liver fibrosis; necroptosis; pyroptosis; quercetin.

FIGURE 1

The chemical structure of quercetin (C₁₅H₁₀O₇).

FIGURE 2

Quercetin-Induced Apoptotic Pathways in Cellular Regulation. The dual apoptotic pathways are within cells: the intrinsic and extrinsic pathways. The intrinsic pathway, activated by internal signals such as DNA damage or mitochondrial disruptions, leads to the activation of caspase-9 and caspase-3. Conversely, the extrinsic pathway is initiated by the external binding of death ligands to cellular death receptors, catalyzing the activation of caspase-8. Quercetin’s role in inducing apoptosis is highlighted through its capacity to disrupt the balance between anti-apoptotic and pro-apoptotic proteins. Specifically, quercetin downregulates the anti-apoptotic protein Mcl-1 and activates the pro-apoptotic protein Bax, while also inhibiting the activity of survival proteins Bcl-2 and Bcl-xL. Moreover, quercetin’s induction of reactive oxygen species (ROS) precipitates the release of cytochrome c and diminishes mitochondrial membrane potential, paving the way for apoptosis. Additionally, quercetin triggers endoplasmic reticulum stress and obstructs the PI3K/Akt signaling pathway, further augmenting apoptotic processes.

FIGURE 3

Quercetin’s Enhancement of Macroautophagy for Cellular Regulation. The quercetin’s dynamic role in bolstering macroautophagy is a critical cellular process for maintaining homeostasis through the degradation and recycling of proteins and organelles. Quercetin modulates the mechanistic target of rapamycin (mTOR) pathway and activates AMP-activated protein kinase (AMPK), leading to decreased mTOR activity and the initiation of autophagy.

FIGURE 4

Regulation of CMA and Macroautophagy by Quercetin. Quercetin notably promotes lysosomal biogenesis, crucial for producing lysosomes that contain the enzymes needed for breaking down cellular metabolite s. Quercetin triggers the nuclear translocation of Transcription Factor EB (TFEB), a key regulator of lysosomal biogenesis and autophagy genes, thus amplifying autophagic activity for improved cellular clearance. Additionally, quercetin modulates the mechanistic target of rapamycin (mTOR) pathway and activates AMP-activated protein kinase (AMPK), leading to decreased mTOR activity and the initiation of autophagy. Through these actions, quercetin serves as a potent facilitator of cellular maintenance and health, highlighting its significant impact on enhancing autophagy for cellular equilibrium and stress management.

FIGURE 5

Quercetin’s Mechanisms in Mitigating Liver Fibrosis. This figure illustrates quercetin’s multifaceted role in combating liver fibrosis, a condition exacerbated by factors like viral hepatitis, alcoholic and non-alcoholic fatty liver disease (NAFLD), through the activation of hepatic stellate cells (HSCs). Central to fibrosis progression, HSCs, upon activation, produce an excess of extracellular matrix metabolites, including collagen, fostering fibrous scar tissue formation within the liver. Quercetin intervenes by inducing apoptosis in activated HSCs, thus diminishing their numbers and fibrogenic output. It notably inhibits the TGF-β1/Smads and PI3K/Akt pathways, crucial for HSC activation and collagen synthesis, and associated with cell survival and proliferation, respectively. Through these actions, quercetin effectively reduces HSC activation and their fibrogenic activity, offering a promising approach to slowing liver fibrosis progression.