Ferroptosis is an iron‐dependent cell death program that is characterized by excessive lipid peroxidation. Triggering ferroptosis has been proposed as a promising strategy to fight cancer and overcome drug resistance in antitumor therapy. Understanding the molecular interactions and structural features of ferroptosis‐inducing compounds might therefore open the door to efficient pharmacological strategies against aggressive, metastatic, and therapy‐resistant cancer. We here summarize the molecular mechanisms and structural requirements of ferroptosis‐inducing small molecules that target central players in ferroptosis. Focus is placed on (i) glutathione peroxidase (GPX) 4, the only GPX isoenzyme that detoxifies complex membrane‐bound lipid hydroperoxides, (ii) the cystine/glutamate antiporter system X_c⁻ that is central for glutathione regeneration, (iii) the redox‐protective transcription factor nuclear factor erythroid 2‐related factor (NRF2), and (iv) GPX4 repression in combination with induced heme degradation via heme oxygenase‐1. We deduce common features for efficient ferroptotic activity and highlight challenges in drug development. Moreover, we critically discuss the potential of natural products as ferroptosis‐inducing lead structures and provide a comprehensive overview of structurally diverse biogenic and bioinspired small molecules that trigger ferroptosis via iron oxidation, inhibition of the thioredoxin/thioredoxin reductase system or less defined modes of action.

Physiological selenium (Se) levels counteract excessive inflammation, with selenoproteins shaping the immunoregulatory cytokine and lipid mediator profile. How exactly differentiation of monocytes into macrophages influences the expression of the selenoproteome in concert with the Se supply remains obscure. THP-1 monocytes were differentiated with phorbol 12-myristate 13-acetate (PMA) into macrophages and (i) the expression of selenoproteins, (ii) differentiation markers, (iii) the activity of NF-κB and NRF2, as well as (iv) lipid mediator profiles were analyzed. Se and differentiation affected the expression of selenoproteins in a heterogeneous manner. GPX4 expression was substantially decreased during differentiation, whereas GPX1 was not affected. Moreover, Se increased the expression of selenoproteins H and F, which was further enhanced by differentiation for selenoprotein F and diminished for selenoprotein H. Notably, LPS-induced expression of NF-κB target genes was facilitated by Se, as was the release of COX- and LOX-derived lipid mediators and substrates required for lipid mediator biosynthesis. This included TXB₂, TXB₃, 15-HETE, and 12-HEPE, as well as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Our results indicate that Se enables macrophages to accurately adjust redox-dependent signaling and thereby modulate downstream lipid mediator profiles.

Rationale: Silybum marianum is used to protect against degenerative liver damage. The molecular mechanisms of its bioactive component, silybin, remained enigmatic, although membrane-stabilizing properties, modulation of membrane protein function, and metabolic regulation have been discussed for decades.

We present a comprehensive account on the evolution of a synthetic platform for a subfamily of ent‐pimaranes. For the most complex member, norflickinflimiod C, five distinct strategies relying on either cationic or radical polyene cyclizations to construct the requisite tricyclic carbon scaffold were explored. Insights from early and late stage oxidative and reductive dearomatization studies ultimately led to a mild, rhodium‐catalyzed arene hydrogenation for the final synthetic route. A Sharpless asymmetric dihydroxylation was found to be suitable to render the platform enantioselective and diversification of a late‐stage key intermediate culminated in the total synthesis of eight ent‐pimaranes in 11–16 steps. These compounds were found to inhibit the formation of pro‐inflammatory leukotrienes and other 5‐lipoxygenase products. Notably, three ent‐pimaranes exhibited low micromolar, non‐redox active ferroptosis inhibition with remarkable structural specificity.

Curcumin is recognized for its diverse biological activities, including the ability to induce apoptosis and ferroptosis. Therefore, it represents a promising candidate for the development of new compounds with neuroprotective and anticancer properties. In order to synthesize mimics with improved pharmacokinetic properties (better solubility and stability than curcumin) here, we present the design and synthesis of novel curcumin analogues named Ethylphosphonate-based curcumin mimics (EPs), which preserve the pharmacophoric features of curcumin. New EP mimics were synthesized by tyrosol- and melatonin-based building blocks using an orthogonal protection approach of the different precursors’ OH functions with good yields and in a few steps. Comparative screenings of the cytotoxic and cytoprotective properties (curcumin was used as a reference compound) were carried out on all new mimics in different cell lines (HeLa, A375, WM266, MDA-MB-231, LX2, and HDF). Assays with inhibitors of ferroptosis (Ferrostatin-1, Fer-1) and apoptosis (Quinoline-Val-Asp-difluorophenoxymethyl ketone, Q-VD), in combination with curcumin, suggested the specific cell death pathway (apoptotic or ferroptotic) of EPs, depending on the aromatic moieties contained in them. Interestingly, EP4 exhibited substantial cytotoxic effects against various human cancer cell lines (HeLa, A375, WM266) while sparing normal cells (HDFs). EP4 displayed a five-times-higher toxicity in triple-negative MDA-MB-231 and LX2 stellate cells than curcumin. The cytotoxicity exerted by EP4 involves only an apoptotic mechanism, contrary to curcumin, which exerts both apoptotic and ferroptotic effects. Additionally, EP4 was also found to be a very potent inhibitor of the ubiquitin-activating enzyme E1, reinforcing the anticancer potential of this compound. Furthermore, EP2 possesses high antioxidant properties, efficiently protects against cell death by ferroptosis, and inhibits the amyloid aggregation involved in AD.

Ferroptosis is an iron-dependent cell death program that is characterized by excessive lipid peroxidation. Triggering ferroptosis has been proposed as promising strategy to fight cancer and overcome drug resistance in anti-tumor therapy. Understanding the molecular interactions and structural features of ferroptosis-inducing compounds might therefore open the door to efficient pharmacological strategies against aggressive, metastatic and therapy-resistant cancer. We here summarize the molecular mechanisms and structural requirements of ferroptosis-inducing small molecules that target central players in ferroptosis. Focus is placed on i) glutathione peroxidase (GPX)4, the only GPX isoenzyme that detoxifies complex membrane-bound lipid hydroperoxides, ii) the cystine/glutamate antiporter system Xc- that is central for glutathione regeneration, iii) the redox-protective transcription factor nuclear factor erythroid 2-related factor (NRF)2, and iv) inducers of the NRF2/heme oxygenase-1 (HO-1) axis that foster heme degradation. We deduce common features for efficient ferroptotic activity and highlight challenges in drug development. Moreover, we critically discuss the potential of natural products as ferroptosis-inducing lead structures and provide a comprehensive overview about structurally diverse biogenic and bio-inspired small molecules that trigger ferroptosis via iron oxidation, inhibition of the thioredoxin/thioredoxin reductase system or less defined modes of action.