Ferroptosis is a novel iron-sensitive subtype of regulated cell death (RCD), persisting under extreme lipid peroxidation and iron/redox imbalances. Unlike apoptosis, necroptosis, and pyroptosis, ferroptosis is a signaling-driven process mediated through iron metabolism imbalance, polyunsaturated fatty acid (PUFA) exceeding oxidation, and defects in its protective systems like Xc-/GSH/GPx4. Specifically, this review establishes that iron-driven ferroptosis is a central underlying pathomechanistic factor in a broad range of human diseases. Significantly, whether its modulation is therapeutic, it is entirely conditional on the specific disease context. Thus, its induction can provide a promising antidote for destructive cancer cells when conjoined with immuno-therapies to boost anticancer immunity. Conversely, iron-mediated ferroptosis suppression is a key factor in countering destructive changes in a whole range of degenerative and acute injuries. Current therapeutic approaches include iron chelators, lipid oxidation inhibitors, GPx4 activators, natural and active compounds, and novel drug delivery systems. However, against all odds and despite its intense therapeutic promise, its translation into a practical medicinal strategy faces many difficulties. Thus, a therapeutic agent specifically focused on its modulation is still lacking. The availability of selective biologic markers is a concern. The challenges in the direct pathologic identification of ferroptosis in a complex in vivo systemic scenario remain. Current avenues for its future development are pathogen infections, the discovery of novel regulating factors, and novel approaches to personalized medicine centered on its organ-level in vivo signatures.

Cystic fibrosis (CF), a severe genetic disorder stemming from mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, is characterized by a complex interplay of chronic inflammation and heightened oxidative stress, resulting in substantial patient morbidity. The diverse array of CFTR mutations, categorized into seven distinct classes based on their functional impact on the CFTR protein, presents a significant obstacle to effective therapeutic intervention. While CFTR modulator therapies offer clinical benefits, their applicability is restricted to specific mutation classes, leaving a considerable portion of the CF patient population with unmet therapeutic needs. This review provides a critical analysis of the intricate role of oxidative stress in CF, meticulously examining its origins, mechanistic pathways and downstream pathological consequences, with particular emphasis on lipid peroxidation (LPO). It elucidates the nuanced connection between LPO and inflammatory processes driven by cellular stressors such as endoplasmic reticulum dysfunction, mitochondrial impairment and persistent bacterial infections. Furthermore, it evaluates the current landscape of therapeutic proposals targeting oxidative stress, including antioxidant interventions, and explores the potential of microRNAs (miRNAs) as novel targets. This review aims to synthesize existing research to provide a comprehensive understanding of oxidative stress involvement in CF pathogenesis while critically appraising the advantages and limitations of current antioxidant therapeutic strategies.

The Ebola virus (EBOV) and the Rabies virus (RABV) are deadly infectious agents impacting human and animal health. Current prevention and control strategies mainly rely on vaccines and antibodies, highlighting the urgent need for effective, low-cost antivirals suitable for therapeutic options. Plant-derived bioactive compounds offer a promising natural source for such candidate antivirals. As a contribution to this antiviral approach, we have characterized the anti-EBOV and anti-RABV activity of a Cranberry extract (CE) endowed with a very high content of bioactive A2-type proanthocyanidin (PAC-A2). The CE inhibited the in vitro infection of both pseudoviruses expressing EBOV-GP or RABV-G glycoproteins and authentic EBOV and RABV. Attachment and entry assays revealed that the extract targets early phases of infection preventing attachment and entry. Noteworthy, synthetic PAC-A2 reproduced the antiviral activity observed with the whole CE. Mechanistic studies then revealed that the CE interacted directly with the ectodomain of EBOV-GP or the RABV-G, suggesting interference with their functions. In support to this hypothesis, fluorescence spectroscopy analysis showed a reduction in intrinsic fluorescence of both EBOV-GP and RABV-G after incubation with synthetic PAC-A2, thus confirming a direct interaction of the viral glycoproteins with PAC-A2. In silico docking simulations further sustained in vitro results by predicting the binding of PAC-A2 into the binding pocket of EBOV-GP and to the trimeric architecture of RABV-G. Together, these results suggest this cranberry extract and bioactive PAC-A2 as potential candidates to be further develop as novel antiviral agents for the prevention of EBOV and RABV infections.