Plant-Derived Compounds Could Crack Osteosarcoma’s Chemotherapy Resistance by Triggering Ferroptosis

Osteosarcoma, the most common primary malignant bone tumor, strikes hardest at adolescents and young adults, and it has stubbornly resisted decades of therapeutic progress. Despite aggressive surgery and multi-agent chemotherapy, survival rates for patients with metastatic or recurrent disease have barely improved since the 1970s, and resistance to frontline drugs such as cisplatin, methotrexate, and doxorubicin remains a central clinical obstacle. Now, a comprehensive review published in Molecular Diversity by Yuwen Dai of Wuhan University and Wanjun Ding of Renmin Hospital of Wuhan University argues that an unusual form of regulated cell death, together with a largely untapped pharmacopeia of plant-derived molecules, could reshape how clinicians approach this devastating disease.

The cell death in question is ferroptosis, a process first named just over a decade ago and now recognized as one of the most consequential discoveries in cancer biology. Unlike apoptosis, ferroptosis is iron-dependent and driven by the accumulation of lipid peroxides in cellular membranes. When the antioxidant machinery that normally keeps these peroxides in check fails, membrane lipids are oxidized faster than they can be repaired, and the cell ruptures in an inflammatory, immunogenic fashion. Because ferroptosis is mechanistically distinct from the pathways that tumors commonly hijack to survive chemotherapy, inducing it offers a way to kill cancer cells that have already become resistant to conventional drugs.

At the heart of ferroptosis regulation lies the system xCT–glutathione–GPX4 axis. The cystine/glutamate antiporter SLC7A11 imports cystine, which cells convert into the antioxidant glutathione; glutathione-dependent peroxidase 4 then detoxifies lipid peroxides. Osteosarcoma cells are notoriously dependent on this axis, and the review catalogs multiple ways the tumor reinforces it. KDM4A-mediated histone demethylation of SLC7A11 suppresses ferroptosis, while m7G modification of the iron-storage protein FTH1 and of pri-miR-26a tunes both iron handling and drug resistance. Long noncoding RNA SNHG14 promotes resistance to the MDM2 inhibitor nutlin-3a by repressing miR-206 and thereby sustaining SLC7A11 expression. Even epitranscriptomic machinery is implicated: METTL3-driven m6A modification contributes to anlotinib resistance through a circFAM120B/miR-330-3p/PRKDC axis that governs ferroptotic sensitivity.

Beyond the core axis, the review maps a broader regulatory network involving Nrf2/HMOX1, p53, MAPK, and STAT3 signaling. The transcription factor Nrf2, long celebrated as a cytoprotective master switch, becomes a double-edged sword in cancer: its activation arms tumor cells with heme oxygenase-1 and other antioxidant defenses that help them evade ferroptosis and withstand radiotherapy. The tumor suppressor p53, by contrast, can repress SLC7A11 and sensitize cells to lipid peroxidation, while MAPK and STAT3 pathways integrate stress signals that either promote or restrain the ferroptotic program. Disrupting STAT3/Nrf2/GPx4 signaling, for example, has been shown to enhance the sensitivity of osteosarcoma cells to cisplatin, providing a mechanistic bridge between cell death biology and chemotherapy response.

What makes the new review distinctive is its systematic cataloging of natural products, compounds derived from plants and other organisms, that can push osteosarcoma cells over the ferroptotic cliff. The authors organize these agents into five chemical classes: flavonoids, terpenoids, alkaloids, naphthoquinones, and isothiocyanates. Each class attacks the ferroptosis machinery from a different angle, and the diversity of mechanisms is striking. Baicalin, a flavonoid from Scutellaria baicalensis, induces ferroptosis through a novel Nrf2/xCT/GPX4 regulatory axis. Naringenin acts via the STAT3-MGST2 pathway, while theaflavin-3,3′-digallate from black tea plays a dual, ROS-mediated role in ferroptosis and apoptosis through MAPK signaling. Bavachin, a prenylated flavonoid, triggers ferroptosis through the STAT3/p53/SLC7A11 axis, and the soy isoflavone genistein inhibits osteosarcoma growth via PPARγ.

Among the terpenoids, several compounds have generated particular excitement. Artesunate, the celebrated antimalarial derived from Artemisia annua, induces ferroptosis in osteosarcoma through NCOA4-mediated ferritinophagy, the autophagic degradation of ferritin that floods cells with free iron. Ursolic acid synergizes with cisplatin through a multistep mechanism involving the same ferritinophagy route, directly attacking drug resistance. Oridonin, from the medicinal herb Rabdosia rubescens, suppresses osteosarcoma growth through a dual approach of ferroptosis and apoptosis, while brusatol modulates the Keap1/Nrf2/SLC7A11 pathway to dismantle the tumor’s antioxidant shield. Celastrol has been shown to overcome 5-fluorouracil resistance by modulating p53-mediated apoptosis and inhibiting the drug efflux pump P-glycoprotein.

The naphthoquinones, a chemically reactive family of pigments, are represented most prominently by shikonin and its derivatives. Shikonin induces ferroptosis through a mitochondrial ROS-regulated HIF-1α/HO-1 axis and simultaneously promotes Nrf2 ubiquitination while inhibiting the xCT/GPX4 axis, effectively striking the tumor’s redox defenses from two directions. Acetylshikonin acts via the lipid peroxidation pathway, and machine learning-guided medicinal chemistry has even yielded a novel berberine derivative that induces SCD-dependent ferroptosis, illustrating how natural product scaffolds can seed next-generation synthetic drugs. On the alkaloid front, berberine synergizes with cisplatin by inhibiting MAPK signaling, curcumin regulates Nrf2/GPX4 signaling to induce both ferroptosis and apoptosis, and sulforaphane, an isothiocyanate from cruciferous vegetables, targets p62 to promote autolysosomal degradation of SLC7A11, a mechanism that directly strips tumor cells of their cystine import capacity.

Perhaps the most forward-looking section of the review concerns the immune microenvironment. Ferroptotic cell death is not a silent affair: oxidized phospholipids released from dying cells act as danger signals that the innate immune system is evolutionarily wired to detect. In osteosarcoma, this opens a genuine therapeutic opportunity, because the tumor microenvironment is increasingly recognized as a determinant of survival, particularly in metastatic disease. Formononetin, a phytoestrogen from legumes, has been shown to enhance cisplatin sensitivity in osteosarcoma by inducing ferroptosis and simultaneously reconstructing the immune microenvironment, a finding that exemplifies the dual strategy the review champions. Cucurbitacin B, meanwhile, modulates M2 macrophage differentiation and attenuates tumor progression through the PI3K/AKT pathway, and curculigoside induces apoptosis and ferroptosis while modulating reactive oxygen species and the tumor microenvironment. The interplay, however, cuts both ways: cystine deprivation can trigger CD36-mediated ferroptosis and dysfunction in tumor-infiltrating CD8-positive T cells, and cancer cells dying from ferroptosis have been reported to impede dendritic cell-mediated anti-tumor immunity in some contexts, underscoring that timing and context of ferroptosis induction will be critical.

The authors are candid about the bottlenecks separating laboratory promise from clinical reality. Mechanistic validation remains insufficient for many compounds, most of which have been studied only in cell lines and xenograft models. Target specificity is poor, since many natural products are promiscuous multi-target agents, a virtue for efficacy but a liability for toxicity prediction. Clinical translation is limited: a small trial of a curcumin formulation combined with ashwagandha root extract in advanced high-grade osteosarcoma, and pre-surgical studies of doxorubicin-curcumin co-loaded lipid nanoparticles, represent early and tentative steps. Batch-to-batch quality consistency of botanical products, a regulatory challenge the U.S. FDA has addressed through dedicated botanical drug guidance, adds another layer of complexity. The review also notes a shortage of rigorous combination therapy strategies, even though the mechanistic logic for pairing ferroptosis inducers with chemotherapy, radiotherapy, photodynamic therapy, or immunotherapy is compelling.

The path forward, the authors propose, lies in precision. Nanomedicine platforms, including bone-targeting exosome nanoparticles, pH-responsive hydrogels for shikonin delivery, eriodictyol-cisplatin coated nanomedicines, and Ca-Mn or Cu-Fe3O4 nanoplatforms that exploit oxidative stress and even cuproptosis, could concentrate ferroptosis-inducing payloads within tumors while sparing healthy tissue. Machine learning-powered compound discovery, already demonstrated with the berberine derivative, could accelerate scaffold optimization. And integrating ferroptosis induction with immune checkpoint blockade or photothermal therapy, as suggested by CRISPR/Cas9 nanoplatform work and cancer-erythrocyte membrane-mimicking nanoparticles, could convert a tumor-killing mechanism into a durable, systemic anti-cancer response. For a disease in which adolescents and young adults still face the poorest odds, the message of this review is that the next breakthrough may come not from an entirely synthetic molecule, but from rediscovering, refining, and re-engineering what nature already provides.

Subject of Research: Natural product-mediated ferroptosis induction and immune microenvironment modulation as a strategy to overcome chemotherapy resistance in osteosarcoma

Article Title: Natural products mediate ferroptosis and immune microenvironment-linked sensitization in osteosarcoma: from chemotherapy resistance to combined therapeutic transformation

Article References: Dai, Y., & Ding, W. (2026). Natural products mediate ferroptosis and immune microenvironment-linked sensitization in osteosarcoma: from chemotherapy resistance to combined therapeutic transformation. Molecular Diversity. https://doi.org/10.1007/s11030-026-11707-y

Image Credits: AI Generated

DOI: 10.1007/s11030-026-11707-y

Keywords: osteosarcoma, ferroptosis, natural products, chemotherapy resistance, GPX4, SLC7A11, Nrf2, STAT3, immune microenvironment, flavonoids, shikonin, artesunate