Gold(I) complexes are historically used as anti-arthritic drugs, with two FDA-approved examples, auranofin (AF) and sodium aurothiomalate. Gold-based complexes have recently emerged as a class of anticancer agents. Their canonical mechanisms of action are closely tied to coordination chemistry, using various ligands that tune the stability, reactivity, and selectivity toward biomolecular targets. Structure-activity relationship (SAR) studies have validated that phosphines, N-heterocyclic carbenes (NHCs), thiolates, ions (anions), and alkynyl ligands orchestrate the cellular uptake, redox modulation, and interactions with key enzymes, such as thioredoxin reductase (TrxR), and other thiol or selenol enzymes through AuS and/or AuSe bond(s). These chemical and biological features endow gold(I) complexes with polypharmacological properties, including disruption of mitochondrial metabolism, induction of oxidative stress, and activation of apoptotic pathways. Importantly, recent studies have shown that some rationally designed gold(I) complexes, including AF, could interact with the immune system, thereby promoting immunogenic cell death (ICD), altering redox-sensitive cytokine signaling, and reshaping the tumor microenvironment (TME) to potentiate antitumor effects of immunotherapies. These promising preclinical data provide a mechanistic rationale for combining gold(I) complexes with immune checkpoint inhibitors (ICIs) and other immunotherapies, which have shifted cancer treatment to a new paradigm. While significant progress has been made, currently, AF is the only one under clinical trials for cancer. In this review, we intend to outline the principles of drug structure design, mechanistic insights, and medicinal chemistry innovations that have driven the field. We also critically discussed current challenges and proposed future directions for advancing gold(I) complexes. We concluded here that integrating medicinal chemistry-driven design with immuno-oncology strategies really holds great promise for translating more gold(I) complexes into more clinically viable anticancer therapeutics.

Although 40-70% of TNBC cases overexpress EGFR, clinical responses to EGFR-targeted therapies have been minimal. This poor efficacy may result from intrinsic resistance mechanisms, inactive EGFR signaling, or reduced EGFR localization on the plasma membrane. To identify genetic determinants of EGFR inhibitor resistance, we performed a genome-wide CRISPR/Cas9 knockout screen in MDA-MB-231 cells. The screen revealed that loss of the redox-regulating enzyme Thioredoxin Reductase 3 (TXNRD3) sensitized TNBC cells to the EGFR inhibitor erlotinib. Functional validation showed that both siRNA-induced knockdown and pharmacological inhibition of TXNRD3 with the FDA-approved drug auranofin significantly enhanced the cytotoxic effects of EGFR inhibitors in EGFR-high TNBC cells. Mechanistically, TXNRD3 depletion or inhibition increased intracellular reactive oxygen species (ROS), leading to oxidation-dependent activation and phosphorylation of EGFR (Y1068) and subsequent activation of downstream signaling pathways in TNBC cells that otherwise lack active EGFR. The combined treatment of auranofin and EGFR inhibitors triggered GSDME-mediated pyroptosis in a ROS-dependent manner. Importantly, the combination of auranofin with erlotinib exhibited potent anti-tumor efficacy in vivo in both MDA-MB-231 xenograft and 4T1.2 syngeneic TNBC models. Collectively, our findings identify TXNRD3 as a redox-dependent regulator of EGFR activity and drug response in TNBC and demonstrate that auranofin-mediated TXNRD3 inhibition can re-activate EGFR signaling, thereby sensitizing TNBC tumors to EGFR-targeted therapy. This study provides a mechanistic rationale for repurposing auranofin in combination with EGFR inhibitors as a novel therapeutic strategy for EGFR-high TNBCs.

Tuberculosis (TB) accounted for almost 1.2 million deaths in 2024. It remains a leading cause of mortality due to an airborne infectious bacterium, Mycobacterium tuberculosis (MTB). Despite the development of vaccines and antibiotics to cure the disease, it remains a major global problem due to the development of several ingenious pathogenic pathways. This comprehensive review introduces the mechanisms of bacterial pathogenesis against the human defence system and the development of drugs against MTB, with particular emphasis on the mechanisms of drug resistance and mutations that render them ineffective globally. There is also a discussion of the MTB lineage and the mutant types. The mechanisms of multidrug resistance and ineffective treatment regimens have driven advances in drug development and alternative therapeutics. New molecules that can potentially disarm MTB have been explored, including SQ109, GuaB2, Q203, Largazole, and Auranofin. In addition, natural compounds, bacteriophage therapy, antimicrobial peptides, and probiotics are also explored to help address the global threat posed by MTB.

Objective: To investigate the mechanism through which timosaponin AⅢ (TAⅢ)-based liposomes loaded with auranofin (AUF) (T-AUF-LPs) induce ferroptosis in anaplastic thyroid carcinoma cells. Methods: T-AUF-LPs were prepared using the thin-film hydration method, and their physicochemical properties and stability were characterized. Additionally, conventional liposomes (C-AUF-Lips) were prepared using cholesterol as the membrane material. Cellular uptake efficiency was evaluated in CAL-62 cells using coumarin-6-labeled liposomes. Cell viability was assessed via CCK-8 assay. The role of ferroptosis was confirmed using the inhibitor Ferrostatin-1 (Fer-1) and flow cytometric analysis of cell death. The expression of ferroptosis-related markers (ACSL4, NCOA4, GPX4) were detected using RT-qPCR and Western blot. Levels of intracellular iron, glutathione (GSH), and lipid peroxidation were measured. A nude mouse tumor xenograft model was established to evaluate the in vivo antitumor efficacy of T-AUF-LPs, and hematoxylin-eosin (HE) staining was performed to assess potential systemic toxicity. Results: T-AUF-LPs appeared as uniformly distributed spherical particles with an average size of (119.40±3.11) nm, which was significantly smaller than that of the conventional liposomes C-AUF-LPs (P＜0.001). The zeta potential of T-AUF-LPs was (-12.07±0.65) mV, lower than that of C-AUF-LPs (P=0.002). Furthermore, CAL-62 cells exhibited significantly enhanced cellular uptake of T-AUF-LPs compared to C-AUF-LPs. Cell experiments demonstrated that among the established groups, i.e., Control, TAⅢ, AUF, AUF+TAⅢ, C-AUF-LPs, and T-AUF-LPs, the T-AUF-LPs group exhibited the lowest half-maximal inhibitory concentration (IC50=0.66 μmol/L) and the highest CAL-62 cell mortality (14.7±1.3)%. Furthermore, this group showed significantly elevated lipid peroxidation (2.07±0.28), increased iron content (4.64±0.17), and markedly reduced glutathione (GSH) levels (0.11±0.05). At the molecular level, mRNA expression of ACSL4 and NCOA4 was up-regulated (13.10±0.94 and 7.52±0.49, respectively), while GPX4 mRNA was down-regulated (0.16±0.21). Consistently, ACSL4 and NCOA4 protein expression was increased (1.30±0.06 and 1.13±0.31, respectively), whereas GPX4 protein expression was decreased (0.31±0.18).Notably, pretreatment with the ferroptosis inhibitor Fer-1 significantly reversed T-AUF-LPs-induced cell death, reducing mortality to (8.8±0.8)%. Animal studies demonstrated that among all groups, tumor growth was most significantly suppressed in the T-AUF-LPs group, which exhibited the smallest tumor volume on day 15 post-inoculation. No significant body weight loss was observed in nude mice, and histopathological assessment of the heart, liver, lungs, and kidneys revealed no apparent toxic damage. In tumor tissues of the T-AUF-LPs group, mRNA expression of ACSL4 and NCOA4 was significantly up-regulated (1.59±0.29 and 8.65±3.48, respectively), while GPX4 mRNA expression was markedly down-regulated (0.11±0.01). Consistently, ACSL4 and NCOA4 protein levels were increased (1.26±0.31 and 1.14±0.39, respectively), whereas GPX4 protein expression was significantly reduced (0.56±0.12). Conclusion: T-AUF-LPs inhibited the growth of anaplastic thyroid carcinoma cells by activating the ferroptosis pathway.

Cryptosporidium parvum (C. parvum), a zoonotic protozoan parasite with a worldwide distribution, causes life-threatening diarrhea in children and immunosuppressed individuals. Although Nitazoxanide (NTZ) is the only FDA-approved drug against C. parvum, it has shown unsatisfactory results. Auranofin (AUR), an FDA-approved drug for rheumatoid arthritis, has a robust anti-protozoal effect through thioredoxin reductase (TrxR) inhibition, inducing oxidative stress and reactive oxygen species (ROS) production, thus causing parasites' apoptosis. The purpose of the present study was to evaluate the effect of AUR on C. parvum in comparison and in combination with NTZ in immunosuppressed mice. Sixty mice were divided into six groups (10 mice each): Normal control, uninfected immunosuppressed, infected control, NTZ, AUR, and combination groups. The combination group showed the highest percentage of oocysts reduction (93.5 %), followed by the AUR group (64.7 %), with the least reduction in the NTZ group (45.4 %). Histological examination of ileal tissues revealed marked restoration of normal histological features in the combination group, and remarkable improvement in the AUR group, with mild improvement in the NTZ group. The combination group also showed the least nod-like receptor protein 3 (NLRP3) immunohistochemical expression, followed by the AUR group, then the NTZ group. Biochemically, the combination and AUR groups showed the highest reduction in interferon gamma (IFN-γ) and interleukin 1β (IL-1β) levels and the highest increase in IL-10 levels, suggesting AUR's anti-inflammatory effect. The AUR group produced the highest levels of malondialdehyde (MDA) and nitric oxide (NO) and the lowest levels of reduced glutathione (GSH), superoxide dismutase (SOD) and TrxR, signifying AUR-induced oxidant effect. In conclusion, AUR achieved superior results regarding different studied parameters compared to NTZ, thus emphasizing its promising anti-cryptosporidial activities, with the best outcomes in the combination group.

The thioredoxin system, comprising thioredoxin (Trx) and thioredoxin reductase (TrxR), is a central regulator of cellular redox homeostasis and plays essential roles in normal brain physiology and redox signaling. In glioblastoma (GBM), this system undergoes profound pathological rewiring, creating a redox dependency that represents a potential therapeutic vulnerability. The overexpression of Trx and TrxR in GBM promotes tumor proliferation, invasion, angiogenesis, and resistance to chemotherapy and radiotherapy, while the endogenous Trx inhibitor, thioredoxin-interacting protein (TXNIP), is frequently downregulated. This imbalance drives redox adaptation and sustains tumor survival under metabolic and therapeutic stress. Pharmacological modulation of the Trx system using synthetic inhibitors, such as auranofin, platinum-based compounds, and PX-12, as well as selected natural compounds including curcumin analogs and flavonoids, has shown efficacy in preclinical GBM models by inducing oxidative stress and enhancing sensitivity to standard therapies. Emerging evidence also suggests that Trx system targeting may modulate the tumor immune microenvironment, providing a rationale for combination strategies with immunomodulatory approaches. Overall, targeting the Trx system represents a promising precision oncology strategy for GBM. Future efforts should focus on the development of brain-penetrant inhibitors, rational combination therapies, and predictive biomarkers to facilitate clinical translation. Given the essential role of the Trx system in normal brain homeostasis, therapeutic targeting requires careful consideration of safety, therapeutic index, and tumor-selective vulnerabilities. This narrative review discusses current evidence on the physiological functions of the Trx system in the brain, its dysregulation in GBM, and its relevance as a precision therapeutic target.

The suppressive microenvironment of AML limits anti-PD-1 efficacy, making pyroptosis induction a key strategy for its remodeling. Isoalantolactone (IAL), a naturally occurring small molecule, has been identified herein to inhibit cytosolic thioredoxin reductase1 (TXNRD1) and trigger pyroptosis in AML cells, thereby enhancing the efficacy of anti-PD-1 antibody therapy. Mechanistically, the α,β-unsaturated carbonyl group of IAL covalently bound to the selenocysteine residue at the position 498 (Sec498) of TXNRD1 through a Michael addition reaction. Clinical sample analysis revealed that TXNRD1 is overexpressed in AML, which correlates with poor prognosis. Additionally, we found that the TXNRD inhibitor auranofin has demonstrated good efficacy against AML. The inhibition of TXNRD1 activates the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ), which, in turn, upregulates the transcription of caspase-3, subsequently increasing the cleavage of gasdermin E to induce pyroptosis via the non-classical pathway in AML cells. Additionally, enhanced caspase-3 activity promotes poly ADP-ribose polymerase 1 (PARP-1) cleavage and upregulates PD-L1 expression, thereby increasing sensitivity to anti-PD-1 monoclonal antibodies. Overall, the current study highlights a promising approach for augmenting therapy using anti-PD-1 monoclonal antibodies in AML by targeting TXNRD1 to induce pyroptosis and ameliorate the immunosuppressive microenvironment.

Praziquantel (PZQ) is currently the only agent for treating schistosomiasis, but it is plagued by suboptimal efficacy to juvenile parasites, looming drug resistance, and inability to prevent reinfection. Thioredoxin glutathione reductase (TGR) is regarded as a promising therapeutic target due to its essential role in maintaining schistosome redox homeostasis. Herein, the crystal structures of Schistosoma japonicum TGR (SjTGR) in multiple redox states and in complex with NADPH, GSH, and the anti-helminthic agent Auranofin were elucidated. Structural analyses identified the hook-shaped conformation at the C-terminal redox center, which DTNB assays further confirmed enhances electron transfer efficiency. Structural and ITC data indicated that R317 was critical for NADPH binding via hydrogen-bond interactions. The analysis also indicated that the structure basis of Auranofin's potency was its tripartite interaction at the redox-active sites. In addition, we investigated the substrate specificity of SjTrx1i and SjTRP14, downstream proteins regulated by SjTGR, and elucidated the structural basis for this specificity by determining their oxidized/reduced structures. Furthermore, in vivo RNAi indicated knockdown of SjTGR or SjTRP14 blocked the survival and oviposition of schistosomes, thus ameliorating egg-induced granulomatous pathology in mice. This work provided a framework for knowledge-based design of novel anti-schistosomals targeting parasite-specific redox vulnerabilities.

Chirality-induced biochemical response has emerged as a prominent research focus. This research demonstrates the chiral self-sorting assembly of atomically precise Au16 supramolecular rings via aurophilic interactions. Enantiomers (MR,RM'R,R)-Au16Cl8 and (PS,SP'S,S)-Au16Cl8 are fabricated through homochiral self-sorting assembly and are unaffected by anion types. But the chiral self-sorting assembly of (MR,RM'A,A)-Au16(PF6)8 and (PS,SP'A,A)-Au16(PF6)8 in a heterochiral system is influenced by anion types. Crucially, (MR,RM'R,R)-Au16Cl8 displayed superior in vitro antitumor efficacy with IC50 = 0.812 ± 0.002 µM against 4T1 cells compared to (PS,SP'S,S)-Au16Cl8 enantiomer. This enantioselectivity stems from asymmetric glutathione (GSH)-catalyzed decomposition of chiral supramolecular Au16 rings in the tumor microenvironment (apparent kinetic constants: kM = 14.97 × 10[-5] min[-1] × M[-1] vs. kP = 8.56 × 10[-5] min[-1] × M[-1] at 8 mM GSH), releasing the thioredoxin reductase (TrxR) inhibitor dppm2Au2Cl2. The chiral Au16 rings induce dual cell death via TrxR-inhibition-mediated apoptosis and GPX4-suppression-driven ferroptosis, validated by ROS (reactive oxygen species) accumulation, lipid peroxidation and caspase-3 activation. (MR,RM'R,R)-Au16Cl8 (20 mg/kg) achieved 55.4% tumor growth inhibition in 4T1-bearing mice with no detectable organ toxicity, outperforming auranofin in biosafety. This work establishes chiral self-sorting Au16 assemblies as promising platforms for enantioselective cancer therapy with high efficacy and low toxicity.

The first comprehensive study of a series of seven mesoionic tetrazolylidene gold(I) chloride complexes (1-7) featuring a range of alkyl and aryl substituents (Me, t-Bu, iPr, Ph, Tol, Dipp, Mes) is reported. Three synthetic pathways enabling access to scarcely explored abnormal 1,3-disubstituted tetrazolium ligand precursors (L1-L7) have been established. All complexes are characterized by NMR spectroscopy, mass spectrometry, and elemental analysis, confirming their composition and purity. Single-crystal X-ray crystallography of six gold(I) complexes (1-6) reveals nearly linear coordination (176.49(11)-179.0(2)°) at the gold(I) center and a distinct geometric arrangement across the series. NMR stability studies with model nucleophiles L-cysteine (Cys) and glutathione (GSH) support the structural findings, demonstrating rapid and complete reaction of complexes 1-7 with thiols, as confirmed by [1]H NMR and ESI-MS. The antiproliferative activity of the obtained complexes (1-7) and selected precursors (L2, L3, L5, L7) has been evaluated using MTT assays against human A2780 (ovarian) and A549 (lung) cancer cell lines, alongside noncancerous VERO E6 kidney cells for comparison. Most of the complexes display high selectivity indices (SI[A2780] = 63.2-86.7) and potent antiproliferative effects in the low submicromolar range against A2780, outperforming cisplatin and matching the activity of auranofin. Overall, the results presented here demonstrate the potential of gold(I) tetrazolylidene-based complexes for medicinal applications.

Colorectal cancer (CRC) remains a major global health challenge, in which chronic inflammation and redox dysregulation are key drivers of tumor progression. Here, we report a rationally designed family of NSAID-derived alkyne ligands coordinated to JohnPhos-gold(I) fragments, affording eight new alkynyl gold(I) derivatives. Complexes based on naproxen, ibuprofen, and salicylic acid derivatives display potent antiproliferative activity against Caco-2/TC7 colon cancer cells, outperforming oxaliplatin and being comparable to auranofin, while showing markedly reduced cytotoxicity in breast cancer lines and nonmalignant cells, thus indicating promising selectivity. Mechanistic studies revealed that the most active complex, [Au(L1)JP] (1), which contains a naproxen-derived alkyne, inhibits thioredoxin reductase (TrxR), triggers ROS overproduction, disrupts mitochondrial membrane potential, and induces G1-phase arrest while only marginally increasing apoptosis. This suggests the involvement of additional forms of cell death or cytostatic effects. Additionally, complex 1 selectively inhibits the enzyme cyclooxygenase-2 (COX-2) over COX-1 and reduces IL-8 expression without affecting PTGS2 transcription, highlighting a post-transcriptional anti-inflammatory action. These results support NSAID-derived alkynyl gold(I) complexes as promising multitarget agents for colorectal cancer intervention, combining disruption and COX-2 modulation.