Unveiling the therapeutic potential of Taxifolin in Cancer: From molecular mechanisms to immune modulation and synergistic combinations.

Background: Taxifolin (TAX), a flavonoid abundant in various medicinal plants, has gained attention for its multifaceted role in cancer therapy and cytoprotection against chemotherapy-induced toxicities. TAX modulates key signaling pathways to regulate several processes within tumors, thus potentially playing an important role in tumor suppression.

Purpose: This review aims to explore the current understanding of TAX's role in cancer therapy including its antitumor mechanisms, synergistic combinations, and cytoprotective effects. The review also addresses the safety profile of TAX, highlights its pharmacokinetic (PK) properties limiting its use, and summarizes the suggested pharmaceutical and chemical solutions to overcome these limitations.

Methodology: A literature review was conducted through searching online databases such as PubMed and Google Scholar using several combinations of relevant keywords related to TAX's potential in anticancer therapy. A total of 84 articles published within the last 15 years were included in this review and analyzed following the PRISMA guidelines.

Results: TAX inhibits tumor proliferation, migration, and invasion via the cGMP-PKG pathway, inducing G1-phase arrest and apoptosis. TAX's anti-angiogenic and pro-apoptotic effects are mediated by downregulating Hif1-α, VEGF, and AKT. Additionally, it can synergize the conventional chemotherapeutic agents, enhancing their efficacy and mitigating drug resistance by inhibiting P-glycoprotein expression. Additionally, TAX demonstrates cytoprotective effects against cisplatin-induced nephrotoxicity and neurotoxicity, cyclophosphamide/pazopanib-induced hepatotoxicity, methotrexate-induced oral mucositis, and doxorubicin-induced cardiotoxicity by inhibiting ferroptosis. TAX further has immunomodulatory effects in the tumor microenvironment, enhancing immune responses and sensitizing tumors to immune checkpoint inhibitors. Advancements in TAX's anticancer effects include introducing novel drug delivery systems and chemical modifications to generate derivatives with improved pharmacological effects.

Conclusion: Clinical trials are needed to confirm TAX's safety and effectiveness in cancer therapy, optimize formulations, and investigate synergistic combinations. Overall, TAX holds promise as a versatile anticancer agent, offering direct anticancer effects and protective benefits against chemotherapy-induced toxicities.