R-(-)-gossypol (AT 101) / Ascentage Pharma - LARVOL DELTA

Modification of Chitosan with (-)-Gossypol and (-)-Gossypol Acetic Acid Using Free-Radical Grafting Method. (PubMed, Int J Mol Sci) - "The content of GS in polymers raised proportionally with increasing amount of GS added to the reaction mixture, thereby enhancing the ability to scavenge free radicals. The type of GS used (GS or GSA) in polymers affected the degree of CS crosslinking (higher for pure GS), polymer solubility (lower for pure GS), the amount of grafted GS (~20% higher for GSA), and antioxidant properties in favor of GSA."

Journal • Oncology

Cotton gland formation genes GbCGF2/3 positively regulate Verticillium wilt resistance through modulating suberin biosynthesis. (PubMed, New Phytol) - "Additionally, the expression of gossypol biosynthetic genes and defense-related genes PDF1.2 and PR4 in the phytohormone jasmonic acid (JA) pathway is also downregulated in GbCGF2/3-silenced or Cas9-mediated knockout plants. In conclusion, GbCGF2/3 positively regulates Verticillium wilt resistance through promoting suberin biosynthesis, gossypol accumulation and expression of JA signaling defense-related genes, providing a novel insight and strategy for breeding cotton cultivars resistant to Verticillium wilt."

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Engineering seed-specific gossypol-free cotton for human-safe consumption by harnessing the dominant-negative effect of the Gl2e mutation. (PubMed, Plant Commun) - "Notably, completely gossypol-free oil and flour can be produced from SSGF seeds without needing a degossypolization treatment. This work establishes a mechanistic foundation for understanding gland development and offers a sustainable path toward enhancing global plant-derived protein and oil resources."

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Whole cottonseed and palmitic and oleic acid supplementation improve production responses during the immediate postpartum in multiparous dairy cows. (PubMed, J Dairy Sci) - "The absence of a synergistic or additive effect when feeding both WCS and supplemental FA could be attributed to their lack of effect on DMI and reduced digestibility of NDF and FA. In conclusion, these results suggest that both WCS and supplemental FA in the diet can enhance milk production in early-lactation dairy cows, with WCS improving milk fat and protein yields and supplemental FA improving milk fat yield."

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Exploring Ferroptosis-Related Genes in Depression: Insights Into Molecular Mechanisms and Potential Therapies. (PubMed, Int J Gen Med) - "We identified five potential small-molecule compounds (VX-702, gossypol, atomoxetine, TWS-119, and ibudilast) that may target these ferroptosis-related pathways...This study provides evidence supporting the involvement of ferroptosis-related mechanisms in depression and proposes a integrative treatment strategy combining targeted molecular interventions with TCM approaches. The findings offer new perspectives for developing therapeutic interventions, particularly for treatment-resistant depression."

Journal • CNS Disorders • Depression • Inflammation • Mood Disorders • Psychiatry

Gossypol acetate Combined with Bevacizumab and FOLFIRI as Second-Line Therapy for Metastatic Colorectal Cancer with TP53 Mutation and LRPPRC Positivity: A Single-Center, Single-Arm Clinical Study (ChiCTR) - P1 | N=20 | Not yet recruiting | Sponsor: The Second Hospital of Hebei Medical University; The Second Hospital of Hebei Medical University

New P1 trial • Colorectal Cancer • Oncology • Rectal Adenocarcinoma • Solid Tumor

A dirigent protein redirects extracellular terpenoid metabolism for defense against biotic challenges. (PubMed, Nat Commun) - "Notably, mutants lacking these dirigent proteins produce gossypol but are devoid of hemigossypolone and heliocides in green organs exhibit heightened susceptibility to multiple biotic stresses, underscoring the enhanced protective role of these metabolites. This study describes a DPs-mediated mechanism of extracellular hydroxylation and highlights the potential ecological advantages of redirecting specialized metabolism extracellularly for enhanced defense against varying types of pathogens and herbivores."

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Cytotoxicity, antioxidant activity, and gene expression effects of gossypol in primary smooth muscle of myometrium from Ovis aries (PSMo24) cells. (PubMed, Reprod Biol) - "In conclusion, gossypol induces dose-dependent cytotoxicity in uterine smooth muscle cells (PSMo24), modulating structural, hormonal, and apoptotic genes without altering basal antioxidant activity. Low concentrations were well tolerated, while higher doses from 7 µg/mL activated pro-apoptotic pathways The results highlight the need for caution in reproductive contexts within the animal field and suggest potential use in oncological therapies."

IO biomarker • Journal • BAX • BCL2 • ER • MYLK • PGR

Structure, tautomerism, and radical scavenging activity of Schiff bases and hydrazones of gossypol. (PubMed, Phys Chem Chem Phys) - "Some of them are 4 times more effective than caffeic acid in their radical scavenging properties. The modification of gossypol by introducing amines and hydrazines containing groups capable of reacting with free radicals allows obtaining promising and highly effective radical scavenging agents."

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Targeting Steroid Receptor Coactivators for the Treatment of Benign Female Reproductive Disorders. (PubMed, Endocr Connect) - "To inhibit SRC activity, natural compounds (e.g., gossypol, bufalin, verrucarin A) and synthetic small molecules (e.g., SI-2, SI-12, MCB-613) have been developed, demonstrating preclinical efficacy across several human diseases...This review summarizes current knowledge of SRC biology in benign gynecologic disorders, outlines their mechanistic roles in disease progression, and highlights opportunities for clinical translation. Targeting SRCs may ultimately represent a novel, non-hormonal, fertility-preserving therapeutic strategy in women's health."

Journal • Endometriosis • Gynecology • Immunology • Polycystic Ovary Syndrome • Solid Tumor • Uterine Leiomyoma • Women's Health • NCOA3

Screening of a Gossypol-Removing Yeast Strain and Characterization of Its Removal Mechanism. (PubMed, Microorganisms) - "Assessment of gossypol removal activity revealed that strain ZYS-3 predominantly removes gossypol through the secretion of extracellular enzymes targeting specific active groups (phenolic hydroxyl groups and aldehyde groups) within the gossypol molecule. These enzymes facilitate oxidation and elimination reactions, leading to the opening of the naphthalene ring and subsequent removal of gossypol."

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Gossypol acetic acid affects locomotor activity by inducing mitophagy-related ferroptosis and apoptosis in zebrafish. (PubMed, Toxicol Sci) - "The in vitro study using PC12 cells also showed that GAA could induce mitochondrial membrane potential rise, ROS generation, apoptosis and ferroptosis. These results indicate that GAA affects locomotor activity by disrupting the nervous system and muscle in zebrafish, and its toxicity is closely related to mitochondria dysfunction, oxidative stress, apoptosis and ferroptosis."

Journal • Oncology

Biochemical and metabolic responses of cotton variety XLZ54 to Thrips tabaci and screening of resistance characterization indicators. (PubMed, Pest Manag Sci) - "This study indicates that XLZ54 has the highest resistance to T. tabaci, and this is closely related to its low nutrient content and its high amounts of insect-resistant substances such as flavonoids, total phenols, gossypol, and tannins after damage. In addition, the seven indicators mentioned above can serve as characterization indices for evaluating the resistance of cotton to T. tabaci, providing a basis for future breeding of cotton varieties resistant to T. tabaci."

Journal • CAT

CRISPR/Cas9-mediated mutation of GhCAD decreases the gossypol content of cottonseed. (PubMed, J Biol Eng) - "Furthermore, we characterized GhMYC2-D09 as a transcription factor that increases gossypol biosynthesis. These findings may provide new insights to further elucidate the regulatory network of gossypol biosynthesis."

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Effects of Gossypol Exposure on Ovarian Reserve Function: Comprehensive Risk Assessment Based on TRAEC Strategy. (PubMed, Toxics) - "The TRAEC risk score of 4.68 classified gossypol as a moderate reproductive toxicant. These findings indicate that gossypol damages ovarian reserve and oocyte competence, with only partial reversibility, highlighting the need for caution in its clinical use."

Journal • Oncology

Knockdown and Inhibition of RNA-Binding Proteins Musashi-1 and Musashi-2 Modulate DNA Repair and Radiosensitize Triple-Negative Breast Cancer (ASTRO 2025) - "Msi proteins are overexpressed and associated with oncogenic signaling in TNBC. Msi targeting – either via knockdown or inhibition – compromised proliferation, motility, and DNA repair and sensitized TNBC cells to irradiation and chemotherapy. Given promising pre-clinical data, Msi inhibition deserves further study as a therapy-sensitizing approach."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • MSI1 • MSI2

From lab to field: Supramolecular probe for gossypol real-time quantification. (PubMed, Biosens Bioelectron) - "The supramolecular probe was effectively utilized for the quantification of trace amounts of gossypol in real samples, such as cottonseed oil and cottonseed meal, yielding satisfactory recovery rates and reproducibility. This innovative approach integrates high analytical performance with practical applicability, providing an essential solution for food safety monitoring."

Journal

Next-Generation Bcl-2 Inhibitors: Design and Evaluation of Indolyl-Triazole Derivatives with Anticancer Potential. (PubMed, ChemMedChem) - "ELISA binding assays further validated the efficacy of R4, R14, and R23, showcasing their potency with IC50 values ranging from 0.25 to 0.63 µM, compared to gossypol and ABT-199 (venetoclax), with IC50 values of 0.6 and 0.038 µM, respectively...Moreover, molecular dynamics simulations reveal low root mean square deviation fluctuations, indicating strong and stable interactions with Bcl-2. These findings underscore the therapeutic potential of R23 as a Bcl-2 inhibitor."

Journal • Oncology

Histopathological examination and transcriptomic profiling reveal gossypol toxicity-responsive genes related to fertility in mice. (PubMed, Front Pharmacol) - "This study strongly links the Dmrt2 gene in reproductive tissues to gossypol resistance, highlighting its potential protective role and advancing the understanding of gene regulation in mouse fertility. Further research and food safety considerations are therefore crucial."

Journal • Preclinical • Hematological Disorders • Metabolic Disorders

Targeting the Tumor Immune Microenvironment in Triple-Negative Breast Cancer: The Promise of Polyphenols. (PubMed, Cancers (Basel)) - "This study also describes differential responses of TNBC cell lines to polyphenol treatment, highlighting the importance of considering genetic variability in therapeutic strategies, as well as the importance of the interaction of polyphenols with the gut microbiome, which may establish the bioavailability and effectiveness of these compounds toward therapeutic outcomes. Further preclinical and clinical studies are warranted to fully elucidate the therapeutic potential of polyphenols and translate these findings into clinical practice, thereby improving outcomes for patients with TNBC worldwide."

IO biomarker • Journal • Review • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CCL2 • PD-L1

Gossypol-based nanocarriers for cancer treatment: advances and future perspectives. (PubMed, J Biomater Sci Polym Ed) - "Finally, the review highlights emerging trends, including exosome-mediated delivery and biomimetic systems, and discusses the future of personalized nanomedicine and translational pathways for clinical adoption. Gossypol-loaded nanocarriers represent a promising frontier in cancer therapy, potentially bridging the gap between natural product efficacy and clinical applicability."

Journal • Review • Oncology

Indole-imidazolone derivatives as dual Mcl-1/COX-2 inhibitors: Design-oriented synthesis, molecular docking, and dynamics studies with potential anticancer and anti-inflammatory activities. (PubMed, Bioorg Chem) - "= 28.44), surpassing celecoxib. Molecular docking and dynamics confirmed strong and stable binding to Mcl-1 and COX-2. In silico ADMET predictions indicated favorable drug-like and pharmacokinetic properties for the active compounds."

Journal • Oncology • ANXA5 • BCL2 • BCL2L1

Synergistic fermentation of cottonseed meal using Lactobacillus mucosae LLK-XR1 and acid protease: Sustainable production of cottonseed peptides and depletion of free gossypol. (PubMed, Food Chem) - "Furthermore, the enrichment of harmful bacteria in CSM was inhibited by the fermentation process, and the ability to improve in vitro fermentation characteristics of cows and in vitro dry matter and crude protein digestibility of pigs was also demonstrated by fermented CSM. Overall, the synergistic fermentation process of CSM with LLK-XR1 and acid protease enhanced its nutritional value and bioavailability, offering a practical solution for utilizing CSM."

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Targeted metabolomic and transcriptomic reveal the regulatory network of ultrasound on polyphenol biosynthesis in tender coconut flesh during storage. (PubMed, Food Chem (Oxf)) - "Furthermore, downregulation of CSE, DFR and CHI reduced contents of luteolin, whereas downregulation of LAR and ANS elevated the contents of catechin and epicatechin. Unraveling the effect of ultrasound on phenolic biosynthesis in the tender coconut flesh at metabolite and transcript levels provides technical and theoretical support for the high-value development and utilization of Hainan coconut resources."

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Protective effect of (±)-gossypol through modulation of VEGF and apoptosis in mice bearing Ehrlich's solid carcinoma. (PubMed, Z Naturforsch C J Biosci) - "Administration of (±)-gossypol (40 mg/kg/day ip) for five consecutive days was well tolerated, with no observable signs of systemic toxicity, such as >5 % weight loss or behavioral abnormalities on mice. These findings revealed that (±)-gossypol, in addition to its tumor suppressive effect, can inhibit pro-angiogenic effects of Ehrlich's ascites carcinoma (EAC) cells and have a protective effect in breast cancer."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • VEGFA