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<front>
<journal-meta>
<journal-id journal-id-type="publisher-id">Front. Pharmacol.</journal-id>
<journal-title>Frontiers in Pharmacology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Pharmacol.</abbrev-journal-title>
<issn pub-type="epub">1663-9812</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="publisher-id">1453426</article-id>
<article-id pub-id-type="doi">10.3389/fphar.2024.1453426</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Pharmacology</subject>
<subj-group>
<subject>Review</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Licochalcone A: a review of its pharmacology activities and molecular mechanisms</article-title>
<alt-title alt-title-type="left-running-head">Liu et al.</alt-title>
<alt-title alt-title-type="right-running-head">
<ext-link ext-link-type="uri" xlink:href="https://doi.org/10.3389/fphar.2024.1453426">10.3389/fphar.2024.1453426</ext-link>
</alt-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" equal-contrib="yes">
<name>
<surname>Liu</surname>
<given-names>Meihua</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>&#x2020;</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2720950/overview"/>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
</contrib>
<contrib contrib-type="author" equal-contrib="yes">
<name>
<surname>Du</surname>
<given-names>Yang</given-names>
</name>
<xref ref-type="aff" rid="aff3">
<sup>3</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>&#x2020;</sup>
</xref>
<role content-type="https://credit.niso.org/contributor-roles/writing-original-draft/"/>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Gao</surname>
<given-names>Dejiang</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="corresp" rid="c001">&#x2a;</xref>
<role content-type="https://credit.niso.org/contributor-roles/Writing - review &#x26; editing/"/>
</contrib>
</contrib-group>
<aff id="aff1">
<sup>1</sup>
<institution>Research Center of Emotional Diseases</institution>, <institution>Shenyang Anning Hospital</institution>, <addr-line>Shenyang</addr-line>, <country>China</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>Shenyang Key Laboratory for Causes and Drug Discovery of Chronic</institution>, <addr-line>Shenyang</addr-line>, <country>China</country>
</aff>
<aff id="aff3">
<sup>3</sup>
<institution>The First Affiliated Hospital of Dalian Medical University</institution>, <addr-line>Dalian</addr-line>, <country>China</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>
<bold>Edited by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/2344379/overview">Jing Wu</ext-link>, Greater Baltimore Medical Center, United States</p>
</fn>
<fn fn-type="edited-by">
<p>
<bold>Reviewed by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/993519/overview">Tetsuhiro Yoshino</ext-link>, Keio University, Japan</p>
<p>
<ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/2778098/overview">Wang Yubo</ext-link>, Jinzhou Medical University, China</p>
</fn>
<corresp id="c001">&#x2a;Correspondence: Dejiang Gao, <email>495462632@qq.com</email>
</corresp>
<fn fn-type="equal" id="fn001">
<label>
<sup>&#x2020;</sup>
</label>
<p>These authors have contributed equally to this work</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>12</day>
<month>08</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>15</volume>
<elocation-id>1453426</elocation-id>
<history>
<date date-type="received">
<day>23</day>
<month>06</month>
<year>2024</year>
</date>
<date date-type="accepted">
<day>02</day>
<month>08</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2024 Liu, Du and Gao.</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Liu, Du and Gao</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<p>Licorice, derived from the root of Glycyrrhiza uralensis Fisch, is a key Traditional Chinese Medicine known for its detoxifying, spleen-nourishing, and qi-replenishing properties. Licochalcone A (Lico A), a significant component of licorice, has garnered interest due to its molecular versatility and receptor-binding affinity. This review explores the specific roles of Lico A in various diseases, providing new insights into its characteristics and guiding the rational use of licorice. Comprehensive literature searches using terms such as &#x201c;licorice application&#x201d; and &#x201c;pharmacological activity of Lico A&#x201d; were conducted across databases including CNKI, PubMed, and Google Scholar to gather relevant studies on Lico A&#x2019;s pharmacological activities and mechanisms. Lico A, a representative chalcone in licorice, targets specific mechanisms in anti-cancer and anti-inflammatory activities. It also plays a role in post-transcriptional regulation. This review delineates the similarities and differences in the anti-cancer and anti-inflammatory mechanisms of Lico A, concluding that its effects on non-coding RNA through post-transcriptional mechanisms deserve further exploration.</p>
</abstract>
<kwd-group>
<kwd>Licochalcone A</kwd>
<kwd>licorice</kwd>
<kwd>anti-cancer</kwd>
<kwd>anti-inflammatory</kwd>
<kwd>targets</kwd>
</kwd-group>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Ethnopharmacology</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="s1">
<title>1 Introduction</title>
<p>The root of <italic>G. inflata</italic> Batal has been a valuable medicinal resource for licorice widely used in Asia and worldwide. Licocalcone A (Lico A) is one of the characteristic component of the root of <italic>Glycyrrhiza inflata</italic>. The application of licorice dates back to ancient civilizations such as Greece and Rome (<xref ref-type="bibr" rid="B2">Armanini et al., 2002</xref>). Today, licorice is widely incorporated into food, medicinal products, health supplements, and cosmetics, recognized for its safety and efficacy. In Traditional Chinese Medicine, licorice is prized for its harmonizing properties, and it has also become popular in dietary applications for its health benefits (<xref ref-type="bibr" rid="B20">Herrera et al., 2009</xref>). Modern applications extend to food additives, tobacco flavoring, and skin depigmentation products (<xref ref-type="bibr" rid="B61">Rizzato et al., 2017</xref>). Its safety has been affirmed by the U.S. Flavor and Extract Manufacturers Association (<xref ref-type="bibr" rid="B56">Pastorino et al., 2018</xref>), solidifying its reputable status and prompting increased research into its pharmacological activities and applications (<xref ref-type="bibr" rid="B56">Pastorino et al., 2018</xref>).</p>
<p>Flavonoids, common in nature (<xref ref-type="bibr" rid="B58">Perezvizcaino and Fraga, 2018</xref>), typically form glycosides in plants or exist in their free form (<xref ref-type="bibr" rid="B78">Vukics and Guttman, 2008</xref>). This structural diversity translates to varied pharmacological activities, including free radical scavenging, especially in flavonoids with catechol structures (<xref ref-type="bibr" rid="B84">Yang et al., 2000</xref>; <xref ref-type="bibr" rid="B51">Mukne et al., 2011</xref>; <xref ref-type="bibr" rid="B11">Cheng et al., 2019</xref>). Chalcones, a specific class of flavonoids, have a 1,3-diphenylpropenone skeleton. Among these, Lico A (<xref ref-type="fig" rid="F1">Figure 1</xref>) stands out with its distinct structure and potent anti-inflammatory potential (<xref ref-type="bibr" rid="B14">Cui et al., 2008</xref>; <xref ref-type="bibr" rid="B66">Siddiqui et al., 2011</xref>; <xref ref-type="bibr" rid="B35">Kumar et al., 2014</xref>; <xref ref-type="bibr" rid="B67">Silva et al., 2018</xref>; <xref ref-type="bibr" rid="B87">Zhang et al., 2019</xref>).</p>
<fig id="F1" position="float">
<label>FIGURE 1</label>
<caption>
<p>Origin and structure of Licochalcone A.</p>
</caption>
<graphic xlink:href="fphar-15-1453426-g001.tif"/>
</fig>
<p>Inflammation, a complex defense response to tissue injury, involves the vascular system and is triggered by inflammatory cytokines and mediators (<xref ref-type="bibr" rid="B17">Gabriele and Pucci, 2017</xref>; <xref ref-type="bibr" rid="B24">Huang et al., 2017</xref>). Studies show that Lico A mitigates LPS-induced effects by inhibiting inflammatory cytokine production and NO through NF-&#x3ba;B pathway suppression. Additionally, Lico A enhances the activity of antioxidant enzymes and protects against oxidative damage and cell death via ERK and Akt pathways (<xref ref-type="bibr" rid="B23">Hu and Liu, 2016</xref>). Furthermore, Lico A exhibits significant anti-tumor effects (<xref ref-type="bibr" rid="B31">Kang et al., 2017</xref>; <xref ref-type="bibr" rid="B82">Wu et al., 2017</xref>; <xref ref-type="bibr" rid="B7">Chen et al., 2018a</xref>), including the induction of apoptosis in cancer cells, regulation of the cell cycle, inhibition of tumor invasion and metastasis, and suppression of tumor angiogenesis (<xref ref-type="bibr" rid="B19">Hao et al., 2015</xref>; <xref ref-type="bibr" rid="B44">Lv et al., 2015</xref>).</p>
<p>Beyond its anti-inflammatory and anti-tumor properties, Lico A also demonstrates bacteriostatic, anti-parasitic, and osteogenic activities. This review summarizes the pharmacological actions and mechanisms of Lico A over the past five years, aiming to deepen the understanding of its bioavailability and inform further research.</p>
</sec>
<sec id="s2">
<title>2 Lico A exerts anticancer activity</title>
<p>Traditional Chinese herbal medicine, with its extensive history in treating tumors, continues to be a significant source of anti-tumor medications. <xref ref-type="bibr" rid="B88">Zhou et al. (2019)</xref>. For example, Lico A is renowned for its potent anti-tumor activity (<xref ref-type="bibr" rid="B15">Daniell et al., 2000</xref>; <xref ref-type="bibr" rid="B9">Chen et al., 2017</xref>). Lico A&#x2019;s anticancer effects manifest through various mechanisms, including inducing apoptosis in tumor cells, regulating the cell cycle to inhibit proliferation, curtailing tumor invasion and metastasis, and suppressing tumor angiogenesis by modulating related protein expression and signaling pathways (<xref ref-type="bibr" rid="B85">Yang et al., 2014</xref>; <xref ref-type="bibr" rid="B32">Kim et al., 2015</xref>; <xref ref-type="bibr" rid="B55">Park et al., 2015</xref>; <xref ref-type="bibr" rid="B76">Tsai et al., 2015</xref>; <xref ref-type="bibr" rid="B86">Yang et al., 2016</xref>; <xref ref-type="bibr" rid="B34">Kojima et al., 2017</xref>). Recent studies have highlighted Lico A&#x2019;s cytostatic effects on human nasopharyngeal carcinoma cells mediated through apoptosis targeting the JNK/p38 pathway (<xref ref-type="bibr" rid="B13">Chuang et al., 2019</xref>).</p>
<p>Invasion and metastasis, key traits of malignant tumors, involve tumor cells detaching from the primary lesion, invading surrounding tissues or distant organs, and proliferating to form metastases. Lico A acts to inhibit this process by restraining cell migration, modulating E-cadherin and vimentin expression, and blocking MAPK and AKT signaling pathways (<xref ref-type="bibr" rid="B48">Mazzucchelli and Brambilla, 2000</xref>; <xref ref-type="bibr" rid="B28">Huang et al., 2019a</xref>). This multifaceted approach significantly reduces migratory and invasive capabilities of cells such as SCC-25. Additionally, tumor blood vessels, vital for supplying oxygen, nutrients, and growth factors, are also targeted by Lico A. Studies by <xref ref-type="bibr" rid="B33">Kim et al. (2010)</xref> demonstrated Lico A&#x2019;s ability to inhibit neovascularization both <italic>in vitro</italic> and <italic>in vivo</italic> by suppressing angiogenesis factors such as IL-6, IL-8, and the VEGFR-2 signaling pathway. The effect of Lico A on different tumors and the specific mechanism of action is shown in <xref ref-type="table" rid="T1">Table 1</xref>.</p>
<table-wrap id="T1" position="float">
<label>TABLE 1</label>
<caption>
<p>The type and mechanism of action of Lico A against cancer.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="center">Type</th>
<th align="center">Cell line</th>
<th align="center">Dosage (&#x3bc;M)</th>
<th align="center">Mechanism</th>
<th align="center">Ref</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="center">Nasopharyngeal carcinoma</td>
<td align="center">HONE-1, NPC-39, and NPC-BM</td>
<td align="center">20&#x2013;80</td>
<td align="center">Target the JNK/p38 pathway and exerts a cytostatic effect</td>
<td align="center">
<xref ref-type="bibr" rid="B13">Chuang et al. (2019)</xref>
</td>
</tr>
<tr>
<td rowspan="4" align="center">Breast Cancer</td>
<td align="center">MDA-MB-231</td>
<td align="center">10&#x2013;100</td>
<td align="center">Cell migration and invasion are inhibited by MAPK and AKT signaling</td>
<td align="center">
<xref ref-type="bibr" rid="B27">Huang et al. (2019b)</xref>
</td>
</tr>
<tr>
<td align="center">MCF-7</td>
<td align="center">20&#x2013;100</td>
<td align="center">Activate the LC3-II signaling pathway while suppressing the PI3K/Akt/mTOR/signaling pathway</td>
<td align="center">
<xref ref-type="bibr" rid="B83">Xue et al. (2017)</xref>
</td>
</tr>
<tr>
<td align="center">3T3/MCF-7</td>
<td align="center">IC<sub>50</sub> &#x3d; 27.57</td>
<td align="center">Endogenous pathway-mediated apoptosis</td>
<td align="center">
<xref ref-type="bibr" rid="B5">Bortolotto et al. (2017)</xref>
</td>
</tr>
<tr>
<td align="center">MCF-7 and MDA-MB-231</td>
<td align="center">10&#x2013;30</td>
<td align="center">passed intracellular mitochondrial apoptosis pathway</td>
<td align="center">
<xref ref-type="bibr" rid="B31">Kang et al. (2017)</xref>
</td>
</tr>
<tr>
<td rowspan="3" align="center">Glioma</td>
<td align="center">M059K/U-251&#xa0;MG/GBM8901</td>
<td align="center">20&#x2013;30</td>
<td align="center">Induced ADAM9 expression and inhibits cell invasion activity through the MEK-ERK signaling pathway</td>
<td align="center">
<xref ref-type="bibr" rid="B25">Huang et al. (2018)</xref>
</td>
</tr>
<tr>
<td align="center">U87</td>
<td align="center">20&#x2013;40</td>
<td align="center">Inhibit the growth of cells by inducing cell cycle arrest in G0/G1 phase and G2/M phase</td>
<td align="center">
<xref ref-type="bibr" rid="B42">Lu et al. (2018)</xref>
</td>
</tr>
<tr>
<td align="center">GSC</td>
<td align="center">5&#x2013;7.5</td>
<td align="center">Caused mitochondrial fragmentation and reduced the membrane potential and ATP production</td>
<td align="center">
<xref ref-type="bibr" rid="B36">Kuramoto et al. (2017)</xref>
</td>
</tr>
<tr>
<td rowspan="5" align="center">Lung cancer</td>
<td align="center">H292</td>
<td align="center">10&#x2013;80</td>
<td align="center">Overexpression of mir-144&#x2013;3p induced upregulation of Nrf2 to promote apoptosis</td>
<td align="center">
<xref ref-type="bibr" rid="B10">Chen et al. (2018b)</xref>
</td>
</tr>
<tr>
<td align="center">A549/H460</td>
<td align="center">20&#x2013;80</td>
<td align="center">Blocked cell cycles progression of the G2/M transition and inducing apoptosis</td>
<td align="center">
<xref ref-type="bibr" rid="B59">Qiu et al. (2017)</xref>
</td>
</tr>
<tr>
<td align="center">A549/H1299</td>
<td align="center">5&#x2013;20</td>
<td align="center">Activated CHOP pathway</td>
<td align="center">
<xref ref-type="bibr" rid="B73">Tang et al. (2016)</xref>
</td>
</tr>
<tr>
<td align="center">A549/WI-38</td>
<td align="center">10&#x2013;20</td>
<td align="center">Inhibition of Akt signaling pathway and expression of downstream transcription factor Sp1</td>
<td align="center">
<xref ref-type="bibr" rid="B26">Huang et al. (2014)</xref>
</td>
</tr>
<tr>
<td align="center">MLE-12</td>
<td align="center">10</td>
<td align="center">Reverse lung injury caused by NNK through the mir-144 and MAPK pathways</td>
<td align="center">
<xref ref-type="bibr" rid="B38">Li et al. (2020)</xref>
</td>
</tr>
<tr>
<td rowspan="2" align="center">Hepatoma</td>
<td align="center">HepG2</td>
<td align="center">10&#x2013;80</td>
<td align="center">Attenuat p38/JNK/ERK signaling pathway</td>
<td align="center" style="color:#0070C0">
<xref ref-type="bibr" rid="B9">Chen et al. (2017),</xref> <xref ref-type="bibr" rid="B79">Wang et al. (2018)</xref>
</td>
</tr>
<tr>
<td align="center">HuH7/HepG2</td>
<td align="center">50</td>
<td align="center">Autophagy induced by ULK1/Atg13 and ROS pathways</td>
<td align="center">
<xref ref-type="bibr" rid="B54">Niu et al. (2018)</xref>
</td>
</tr>
<tr>
<td align="center">Malignant pleural mesothelioma</td>
<td align="center">MSTO-211H/H28</td>
<td align="center">10&#x2013;40</td>
<td align="center">Apoptosis was regulated by down-regulating the expression of Sp1</td>
<td align="center">
<xref ref-type="bibr" rid="B32">Kim et al. (2015)</xref>
</td>
</tr>
<tr>
<td rowspan="2" align="center">Gastric cancer</td>
<td align="center">MKN45/SGC7901/GES-1</td>
<td align="center">15&#x2013;60</td>
<td align="center">Blocked the Akt/HK2 pathway</td>
<td align="center">
<xref ref-type="bibr" rid="B82">Wu et al. (2017)</xref>
</td>
</tr>
<tr>
<td align="center">BGC-823</td>
<td align="center">20&#x2013;100</td>
<td align="center">Caused activation of ERK, JNK and p38 MAPK</td>
<td align="center">
<xref ref-type="bibr" rid="B19">Hao et al. (2015)</xref>
</td>
</tr>
<tr>
<td rowspan="2" align="center">Oral cancer</td>
<td align="center">HSC4/HN22</td>
<td align="center">10&#x2013;40</td>
<td align="center">Downregulation of Sp1 expression induces apoptotic cell death in OSCC cells</td>
<td align="center">
<xref ref-type="bibr" rid="B12">Cho et al. (2014)</xref>
</td>
</tr>
<tr>
<td align="center">SCC-25</td>
<td align="center">25&#x2013;100<xref ref-type="table-fn" rid="Tfn1">
<sup>a</sup>
</xref>
</td>
<td align="center">Decreased the expression of mesenchymal markers N-cadherin</td>
<td align="center">
<xref ref-type="bibr" rid="B64">Shen et al. (2014)</xref>
</td>
</tr>
<tr>
<td align="center">Bladder cancer</td>
<td align="center">T24/5637</td>
<td align="center">20&#x2013;60</td>
<td align="center">Induced ROS-dependent G2/M phases arrest and apoptosis</td>
<td align="center">
<xref ref-type="bibr" rid="B29">Jiang et al. (2014),</xref> <xref ref-type="bibr" rid="B21">Hong et al. (2019)</xref>
</td>
</tr>
<tr>
<td align="center">Cervical cancer</td>
<td align="center">FaDu</td>
<td align="center">25&#x2013;125</td>
<td align="center">Induced TRAIL expression was mediated in part by an MAPK signaling pathway involving ERK1/2 and p38</td>
<td align="center">
<xref ref-type="bibr" rid="B55">Park et al. (2015)</xref>
</td>
</tr>
<tr>
<td align="center">Lymphoma</td>
<td align="center">T24</td>
<td align="center">20&#x2013;80</td>
<td align="center">Induce mitochondrial dysfunction, decreased mitochondrial membrane potential</td>
<td align="center">
<xref ref-type="bibr" rid="B80">Wang et al. (2015),</xref> <xref ref-type="bibr" rid="B86">Yang et al. (2016)</xref>
</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="Tfn1">
<label>
<sup>a</sup>
</label>
<p>&#x3bc;g/mL.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<p>In recent years, research into Lico A&#x2019;s anti-cancer activity has deepened, broadening its scope of anti-cancer effects. Novel advancements have been made in understanding Lico A&#x2019;s role against oral and nasopharyngeal cancers (<xref ref-type="bibr" rid="B33">Kim et al., 2010</xref>; <xref ref-type="bibr" rid="B13">Chuang et al., 2019</xref>). Cancer cells&#x2019; inherent ability to sustain growth signals and perpetually proliferate underscores the significance of inhibiting their proliferation in cancer treatment. Through an examination of anti-cancer mechanisms and targets, it is evident that Lico A primarily exerts its anti-cancer effect by inducing apoptosis and impeding the cell cycle. The mitochondrial apoptotic pathway is a central conduit through which Lico A induces apoptosis.</p>
</sec>
<sec id="s3">
<title>3 Lico A exerts anti-inflammatory activity</title>
<p>Inflammation is a common and significant pathological response that underlies many conditions, including surface infections and organ-specific ailments such as pneumonia, hepatitis, and nephritis. It involves a delicate balance between proinflammatory factors and the body&#x2019;s defense mechanisms, which influences the onset, progression, and resolution of inflammation. The NF-&#x3ba;B and Nrf2 pathways play crucial roles in the development of inflammation, and the unique structure of Lico A provides strong anti-inflammatory activity by modulating these pathways.</p>
<sec id="s3-1">
<title>3.1 Lico A achieves anti-inflammatory effects by regulating NF-&#x3ba;B pathway</title>
<p>NF-&#x3ba;B, a nuclear transcription factor widely distributed in various cell types, orchestrates the transcription and expression of genes involved in processes such as cell proliferation, differentiation, and immune response (<xref ref-type="bibr" rid="B46">Maracle et al., 2017</xref>; <xref ref-type="bibr" rid="B79">Wang et al., 2018</xref>). The NF-&#x3ba;B signaling pathway consists of NF-&#x3ba;B, Inhibitor of NF-&#x3ba;B (I&#x3ba;B), and I&#x3ba;B kinases (IKK). In an inactive state, the NF-&#x3ba;B dimer is bound to I&#x3ba;B. Cellular stimulation leads to IKK activation, promoting the phosphorylation and ubiquitination of I&#x3ba;B, followed by its degradation, freeing the NF-&#x3ba;B dimer to bind to target genes and regulate their expression (<xref ref-type="bibr" rid="B52">Napetschnig and Wu, 2013</xref>). Activation of the NF-&#x3ba;B pathway is linked to apoptosis and chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and asthma (<xref ref-type="bibr" rid="B70">Su et al., 2018</xref>).</p>
<p>Studies have shown that Lico A can inhibit TNF-&#x3b1;-induced NF-&#x3ba;B transcriptional activity, possibly by suppressing IKK activation and I&#x3ba;B degradation (<xref ref-type="bibr" rid="B75">Tsai et al., 2014</xref>). Lico A also inhibits the secretion of IL-1&#x3b2;, IL-6, and TNF-&#x3b1; inflammatory cytokines by down-regulating TLR-4 expression and inhibiting the TLR-4/NF-&#x3ba;B inflammatory signaling pathway (<xref ref-type="bibr" rid="B45">Lv et al., 2019</xref>). Moreover, Lico A has shown significant inhibition in LPS-induced microglial cell line BV-2 phosphorylation, suggesting a neuroprotective pharmacological activity (<xref ref-type="bibr" rid="B24">Huang et al., 2017</xref>).</p>
</sec>
<sec id="s3-2">
<title>3.2 Lico A achieves anti-inflammatory effects by regulating Nrf2 pathway</title>
<p>Nrf2, part of the Cap-n-Collar (CNC) regulatory protein family, is a critical transcription factor for cellular antioxidant stress (<xref ref-type="bibr" rid="B50">Moi et al., 1994</xref>). Under normal conditions, it remains inactive, bound to Keap1 in the cytoplasm. External stimuli or oxidative stress trigger Nrf2&#x2019;s dissociation from Keap1, followed by phosphorylation and nuclear transfer. Nrf2 then binds to the antioxidant response element (ARE), initiating the expression of phase II metabolic enzymes and antioxidants, thereby enhancing the body&#x2019;s resistance to oxidative stress (<xref ref-type="bibr" rid="B77">Tu et al., 2019</xref>). The anti-inflammatory impact of the Nrf2 pathway mainly stems from Nrf2 antioxidant pathway activation, which reduces NF-&#x3ba;B&#x2019;s stress-sensitive expression by lowering I&#x3ba;B phosphorylation and subsequently diminishing inflammation (<xref ref-type="bibr" rid="B8">Chen et al., 2006</xref>). Nrf2 and NF-&#x3ba;B pathways mutually inhibit each other (<xref ref-type="bibr" rid="B57">Pedruzzi et al., 2012</xref>).</p>
<p>Research has uncovered that Lico A&#x2019;s anti-arthritis effects depend on the activation of the Keap1-Nrf2 signaling pathway through p62 phosphorylation at the Ser349 site (<xref ref-type="bibr" rid="B70">Su et al., 2018</xref>). In the context of neuroinflammation, Lico A protects OGD/R-stimulated rat primary cortical neurons, and counters oxidative stress-induced neuronal damage, and inflammatory reactions by activating the SIRT1/Nrf2 signaling pathway and inhibiting its downstream NF-&#x3ba;B signaling pathway (<xref ref-type="bibr" rid="B40">Liu D. et al., 2018a</xref>). <xref ref-type="table" rid="T2">Table 2</xref> illustrates the effect of Lico A on different inflammations and the specific mechanisms of action.</p>
<table-wrap id="T2" position="float">
<label>TABLE 2</label>
<caption>
<p>The type and mechanism of action of Lico A against inflammation.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="center">Type</th>
<th align="center">Cell model</th>
<th align="center">Animal model</th>
<th align="center">Mechanism</th>
<th align="center">Ref</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="center">Asthma</td>
<td align="center">TNF-&#x3b1; and IL-4 induced BEAS-2B</td>
<td align="center">BALB/c mice were sensitized with ovalbumin</td>
<td align="center">Inhibited Th2-associated cytokines</td>
<td align="center">
<xref ref-type="bibr" rid="B28">Huang et al. (2019a)</xref>
</td>
</tr>
<tr>
<td align="center">Liver injury</td>
<td align="center">-</td>
<td align="center">LPS/GalN-induced C57BL/6 mice</td>
<td align="center">Inhibition of TLR4-MAPK and NF-&#x3ba;B and Txnip-NLRP3 signaling pathways</td>
<td align="center">
<xref ref-type="bibr" rid="B45">Lv et al. (2019)</xref>
</td>
</tr>
<tr>
<td align="center">Mastitis</td>
<td align="center">LPS induced mMEC</td>
<td align="center">LPS perfused BALB/c mice</td>
<td align="center">Inhibited the MAPK and AKT/NF-&#x3ba;B signaling pathways</td>
<td align="center">
<xref ref-type="bibr" rid="B18">Guo et al. (2019)</xref>
</td>
</tr>
<tr>
<td rowspan="3" align="center">Neuroinflammation</td>
<td align="center">LPS induced RAW 264.7 and BV-2</td>
<td align="center">-</td>
<td align="center">Protect neurons from A&#x3b2;- and LPS/IFN-&#x3b3;-induced toxicity and apoptosis</td>
<td align="center">
<xref ref-type="bibr" rid="B42">Lu et al. (2018)</xref>
</td>
</tr>
<tr>
<td align="center">Primary cultured rat cortical neurons were exposed to OGD/R</td>
<td align="center">-</td>
<td align="center">Counteracts OGD/R-mediated Downregulation of SIRT1, Nrf2 and HO-1, and upregulation of p65</td>
<td align="center">
<xref ref-type="bibr" rid="B41">Liu et al. (2018b)</xref>
</td>
</tr>
<tr>
<td align="center">BV-2 cells stimulated with LPS</td>
<td align="center">Wister rats was given the injection of LPS</td>
<td align="center">Blocked the phosphorylation of ERK1/2 and p65</td>
<td align="center">
<xref ref-type="bibr" rid="B24">Huang et al. (2017)</xref>
</td>
</tr>
<tr>
<td align="center">Acne</td>
<td align="center">P. acnes induced primary mouse macrophages and SZ95</td>
<td align="center">P. acnes induces ear swelling in C57BL/6 mice</td>
<td align="center">Inhibited NLRP3 inflammasome</td>
<td align="center">
<xref ref-type="bibr" rid="B37">Lee et al. (2018)</xref>
</td>
</tr>
<tr>
<td align="center">Arthritis</td>
<td align="center">RASFs</td>
<td align="center">Collagen-induced arthritis model of DBA/1 mice</td>
<td align="center">Activate of Keap1-Nrf2 signaling</td>
<td align="center">
<xref ref-type="bibr" rid="B70">Su et al. (2018)</xref>
</td>
</tr>
<tr>
<td align="center">Acute kidney injury</td>
<td align="center">-</td>
<td align="center">C57BL/6 mice model of LPS-induced AKI</td>
<td align="center">Inhibited LPS-induced NF-&#x3ba;B activation</td>
<td align="center">
<xref ref-type="bibr" rid="B23">Hu and Liu (2016)</xref>
</td>
</tr>
<tr>
<td align="center">Ulcerative colitis</td>
<td align="center">-</td>
<td align="center">DSS -induced ulcerative colitis</td>
<td align="center">Downregulation of NF-&#x3ba;B pathway and upregulation of nuclear factor Nrf2 pathway</td>
<td align="center">
<xref ref-type="bibr" rid="B40">Liu et al. (2018a)</xref>
</td>
</tr>
<tr>
<td align="center">Skin inflammation</td>
<td align="center">HT1080/HDF</td>
<td align="center">post-shave irritation model</td>
<td align="center">Decreased NF-&#x3ba;B and PGE2 secretion</td>
<td align="center">
<xref ref-type="bibr" rid="B71">Sulzberger et al. (2016)</xref>
</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
</sec>
<sec id="s4">
<title>4 Other pharmacological activities of Lico A</title>
<sec id="s4-1">
<title>4.1 Improve obesity and lower blood glucose</title>
<p>Obesity, a significant risk factor for chronic diseases including cardiovascular ailments, hypertension, osteoarthritis, specific cancers, and diabetes, is increasingly prevalent worldwide (<xref ref-type="bibr" rid="B72">Tang et al., 2017</xref>). It also contributes to nonalcoholic fatty liver disease (NAFLD) and hepatic steatosis (<xref ref-type="bibr" rid="B60">Reccia et al., 2017</xref>). Research has shown that Lico A treatment in high-fat diet (HFD)-induced obese mice reduces body weight and decreases inguinal and epididymal adipose tissue compared to HFD-treated mice. Additionally, Lico A improves hepatic steatosis, regulates serum triglycerides, low-density lipoproteins, free fatty acids, and lowers fasting blood glucose levels (<xref ref-type="bibr" rid="B43">Luo et al., 2019</xref>). Lico A&#x2019;s specific lipid-lowering mechanism involves activating the SIRT1/AMPK pathway, reducing fatty acid synthesis, and enhancing lipolysis and beta-oxidation in hepatocytes (<xref ref-type="bibr" rid="B39">Liou et al., 2019</xref>).</p>
<p>Inducing the browning of white adipose tissue (WAT) represents a promising strategy for obesity treatment (<xref ref-type="bibr" rid="B30">Kajimura et al., 2010</xref>; <xref ref-type="bibr" rid="B3">Bartelt et al., 2011</xref>). Lico A enhances the expression of brown fat markers, reducing obesity and restoring metabolic equilibrium (<xref ref-type="bibr" rid="B37">Lee et al., 2018</xref>).</p>
</sec>
<sec id="s4-2">
<title>4.2 Anti-bacterial and fungal effects</title>
<p>Salmonellosis, caused by multi-drug-resistant <italic>Salmonella Typhimurium</italic>, poses a global public health threat (<xref ref-type="bibr" rid="B4">Behravesh et al., 2014</xref>). Lico A inhibits the growth of <italic>S. Typhimurium</italic> at MIC levels of 62.5&#x2013;1,000&#xa0;&#x3bc;g/mL, with an MBC value &#x3e; 1,000&#xa0;&#x3bc;g/mL (<xref ref-type="bibr" rid="B22">Hosseinzadeh et al., 2018</xref>). Additionally, Lico A exhibits substantial antifungal activity against <italic>Candida</italic> albicans, inhibiting biofilm formation by 35%&#x2013;60%, and suppressing yeast-hyphal transformation and protease secretion (<xref ref-type="bibr" rid="B62">Seleem et al., 2016</xref>).</p>
</sec>
<sec id="s4-3">
<title>4.3 Antiparasitic effect</title>
<p>Toxoplasma gondii, the causative agent of toxoplasmosis, poses significant public health challenges (<xref ref-type="bibr" rid="B1">Ajzenberg et al., 2016</xref>). Lico A effectively inhibits T. gondii proliferation in a dose- and time-dependent manner with low cytotoxicity against HFF host cells (<xref ref-type="bibr" rid="B65">Si et al., 2018</xref>). Additionally, Lico A reduces the total number of Schistosoma mansoni eggs, likely by increasing ROS production and inducing the death of adult Schistosoma mansoni (<xref ref-type="bibr" rid="B69">Souza et al., 2017</xref>).</p>
</sec>
<sec id="s4-4">
<title>4.4 Strengthen bone formation and increase bone mass</title>
<p>Osteoporosis, characterized by loss of bone microstructure, heightens fracture risk (<xref ref-type="bibr" rid="B68">Smith and Walker, 1976</xref>). The role of bone marrow mesenchymal stem cells (BMSCs) in osteoporosis has drawn increasing attention. Lico A exerts a potent influence on BMSC osteogenic differentiation and mineralization by up-regulating FasL, and further modulating ERK and GSK-3&#x3b2;-catenin. Through the activation of intraosseous bone formation and partial inhibition of bone resorption in an acute estrogen deficiency model, Lico A administration restores or protects bone mass in disease states (<xref ref-type="bibr" rid="B49">Ming et al., 2015</xref>).</p>
</sec>
<sec id="s4-5">
<title>4.5 Intestinal protective activity</title>
<p>In a recent study, the intestinal protective effect of Lico A was revealed. It was indicated that Lico A could promote intestinal epithelial renewal to exert intestinal protective effect. The mechanism involves regulating T-UCRs (transcripts from ultra-conserved regions) (<xref ref-type="bibr" rid="B81">Wang et al., 2024</xref>).</p>
</sec>
</sec>
<sec sec-type="discussion" id="s5">
<title>5 Discussion</title>
<p>Anti-cancer and anti-inflammatory properties are the main characteristic bioactivities of Lico A, compared with other pharmacological activities. It has been reported that there is a close relationship between inflammation and cancer. On one hand, the persistent inflammatory microenvironment instigates tumors by initiating specific genetic mutations (<xref ref-type="bibr" rid="B6">Botta et al., 2016</xref>). On the other, a growing body of evidence indicates that tumor-related inflammation promotes angiogenesis and metastasis. This loop regulation suggests that Lico A has great potential in cancer prevention for its action of mechanism. The NF-&#x3ba;B pathway, recognized as a classical inflammation pathway, is a key channel through which Lico A exerts its effects against inflammation conditions such as hepatitis, neuroinflammation, and mastitis (<xref ref-type="bibr" rid="B63">Sen and Baltimore, 1986</xref>). The MAPK pathway, implicated in both inflammation and cancer, is another target of Lico A. By influencing these targets, Lico A delivers either anti-inflammatory or anti-cancer effects.</p>
<p>In addition to anti-inflammation and anti-cancer activities, Lico A can also elicit other activities like Anti-bacterial and fungal, Antiparasitic, and intestinal protective effects. However, investigations on these bioactivities are relatively few and lack systematic in-depth studies to fully demonstrate the potential of Lico A, which hindered the further development as a natural bioactive molecule and becomes the key limitation for current research of Lico A.</p>
<p>In addition to inflammation and cancer, recent studies showed the modulatory effect of Lico A on Post-transcriptional regulation. Post-transcriptional regulation refers to the regulation of gene expression after RNA transcription and is a characteristic of gene expression in eukaryotes (<xref ref-type="bibr" rid="B16">Dykes and Emanueli, 2017</xref>). The initial transcript must undergo a series of processes before transforming into a functional mature mRNA, serving as a template for protein translation (<xref ref-type="bibr" rid="B47">Masamha and Wagner, 2017</xref>). Various mechanisms regulate and control the type and quantity of gene expression during this process. Current research focuses on non-coding RNA (ncRNA) such as miRNA, lncRNA, and circRNA (<xref ref-type="bibr" rid="B74">Tezcan et al., 2019</xref>). It is concluded that Lico A can regulate the Nrf2 and MAPK pathways by modulating miR-144, indicating that Lico A has the potential to regulate ncRNA, providing new avenues for studying its pharmacological mechanisms. Moreover, a recent study shows that Lico A can modulate T-UCR regulation. As T-UCRs are also non-coding RNAs and have good conservative characteristics among rats, mice, and humans, playing a fundamental and primary role in gene regulation, more research should be performed to explore the effect of Lico A on posttranscriptional gene regulation.</p>
</sec>
</body>
<back>
<sec id="s6">
<title>Author contributions</title>
<p>ML: Writing&#x2013;original draft. YD: Writing&#x2013;original draft. DG: Writing&#x2013;review and editing.</p>
</sec>
<sec sec-type="funding-information" id="s7">
<title>Funding</title>
<p>The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.</p>
</sec>
<sec sec-type="COI-statement" id="s8">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec sec-type="disclaimer" id="s9">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
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