Ferroptosis−associated inflammation activates myofibroblasts, which secrete matricellular proteins such as periostin and fibronectin

The gap

Evidence profile

Sourced from the future work of the source papers, classified as general, drawn from work published between 2024 and 2026, spanning 3 journals. Those papers have been cited 85 times in total.

Supporting evidence — 5 representative gaps

• Breaking the cycle of fibrosis: Ferroptosis as a therapeutic target (Review) (2026) · International Journal of Molecular Medicine · doi

  Fibrosis, a core pathological process that drives chronic diseases toward organ failure, is characterized by the abnormal deposition of EcM and involves three interconnected phases: Inflammation, proliferation and remodeling. Recent studies have shown that ferroptosis plays a key role in the fibrotic process. The present review systematically summarizes the process of fibrosis, the major mechanisms of ferroptosis and its role in fibrosis, and discusses therapeutic strategies and novel treatment modalities that target ferroptosis for the intervention of fibrosis. current therapeutic approaches primarily focus on two strategies: Protecting parenchymal cells during the inflamma‑ tory phase and eliminating activated effector cells during the proliferative phase. Both strategies target three core regulatory nodes: Iron metabolism pathways, lipid peroxidation pathways and antioxidant systems. Additionally, interventions targeting 12 FENG et al: FERROPTOSIS MECHANISMS AND THERAPIES FOR FIBROSIS macrophage represent a currently prominent strategy. Inhibiting macrophage polarization or eliminating polarized macrophages via the mechanism of ferroptosis can also alleviate fibrosis. Novel ferroptosis‑modulating therapies are evolving in multi‑dimensional directions. In the field of delivery system innovation, engineered exosomes offer unique advantages. MSc‑Exos achieve precise regulation of HScs ferroptosis by delivering functional RNAs (such as miR‑499a‑5p and miR‑144‑3p) and proteins (such as BECN1). S‑RBD‑modified exosomes exert dual regulatory effects in pulmonary fibrosis by suppressing SMAd2/Akt signaling via miR‑486‑5p. concurrently, nanodelivery platforms are advancing precision medicine. For instance, selenium‑doped silica nanoparticles inhibit myocardial ferroptosis by restoring mitochondrial function, while naringenin‑loaded nanoparticles eliminate activated HScs via autophagy‑dependent ferroptosis pathways. These innovations are steering ferroptosis‑targeted therapies toward greater specificity and efficacy. Despite the promise of ferroptosis modulation in fibrosis treatment, clinical translation faces challenges. First, off‑target effects of existing delivery systems risk damaging healthy parenchymal cells, necessitating improved targeting through surface ligand modifications or organ‑specific promoters. Second, dense EcM barriers impede drug penetration, driving the development of MMP‑responsive nanocarriers or ultra‑ sound microbubble‑mediated delivery systems. Future research should prioritize intelligent nanoplatforms, gene‑editing technologies and the integration of single‑cell sequencing with spatial transcriptomics to map organ‑specific regulatory networks. By bridging foundational discoveries with clinical precision medicine, these efforts may unlock transformative therapies for fibrosis.

  generalfuture work
  Keywords: ferroptosis fibrosis therapies process organ strategies target cells regulatory pathways systems delivery core toward three
• Ferroptosis in idiopathic pulmonary fibrosis: mechanisms, impact, and therapeutic opportunities (2025) · Frontiers in Immunology · cited 31× · doi

  Ferroptosis−associated inflammation activates myofibroblasts, which secrete matricellular proteins such as periostin and fibronectin. These proteins accumulate in the lung interstitium, and drive matrix stiffening and epithelial stress (129). This remodeled, rigid extracellular matrix drives nuclear translocation of YAP and TAZ, the Hippo pathway effectors, which in turn induce glycolytic and glutaminolytic genes that support myofibroblast survival and ECM production (171). Simultaneously, oxidative modifications of Ferroptosis, an iron−dependent, lipid peroxidation–driven form of regulated c ell deat h, has emerged as a key pathophysiological mechanism in IPF, linking alveolar epithelial injury to persistent inflammation, macrophage activation, and fibrotic remodeling of the lung parenchyma (7). This review integrates core mechanisms—dysregulated iron metabolism, compromised antioxidant defenses, enzymatic and non −enzymatic lipid peroxidation, and mechanotransduction via

  generalfuture work
  Keywords: ferroptosis ammation proteins lung matrix epithelial iron lipid peroxidation enzymatic associated activates broblasts secrete matricellular
• Ferroptosis-immune-metabolic axis in asthma: mechanistic crosstalk, endotype-specific regulation, and translational targeting (2026) · Frontiers in Immunology · cited 15× · doi

  The recognition of ferroptosis as a critical mechanistic link between dysregulated metabolism, immune activation, and chronic airway inflammation establishes the Ferroptosis-Immune- Metabolic Axis as a transformative conceptual framework for understanding asthma pathogenesis. This integrative perspective elucidates how iron-dependent lipid peroxidation not only initiates epithelial damage but also propagates inflammatory signaling and metabolic reprogramming, creating a self-reinforcing cycle of disease progression. Key findings underscoring this paradigm include the dual role of oxidative metabolites as both effectors and amplifiers of immunity, the substantial therapeutic potential of ferroptosis inhibition, and the emergence of peroxidation-related biomarkers for predictive patient stratification. Despite the significant progress in unraveling the role of ferroptosis in asthma, several critical research gaps remain to be addressed. First, the functional role of ferroptosis in distinct asthma subtypes—specifically pediatric asthma and asthma-COPD overlap syndrome (ACOS)—has not been clearly defined. Current studies primarily focus on adult asthma populations, leaving uncertainties about whether ferroptosis exhibits subtype-specific mechanisms or regulatory patterns in these understudied groups. Second, while single-cell sequencing technologies have revealed heterogeneity in ferroptotic cells (e.g., differences across airway epithelial cell subtypes), the functional validation of these subtype-specific ferroptotic characteristics is lacking. This gap limits the translation of observational findings into mechanistic insights and targeted interventions. To advance this conceptual framework and translate these insights into clinical practice, future research should prioritize the following strategic directions: 1. Spatial Mapping of Ferroptosis: The application of spatial multi-omics platforms and advanced imaging technologies will be essential to elucidate cell- and zone- specific ferroptosis signatures within the asthmatic airway microenvironment. These approaches should clarify the spatial relationships between ferroptotic activity, immune infiltrates, and metabolic alterations, thereby refining our understanding of the proposed axis within its architectural context. 2. Genetic and Metabolic Targeting: The development of cell-specific ferroptosis loss-of-function models (e.g., epithelial- or immune-specific GPX4 or ACSL4 knockout systems) will enable precise dissection of compartment- specific contributions to inflammation and metabolic dysregulation. These investigations will facilitate the design of targeted therapeutic interventions tailored to specific cellular mechanisms. 3. Combination Immuno-Ferroptosis Therapy: There is a compelling need to evaluate rational drug combinations that simultaneously target ferroptosis and immune pathways. Strategic combinations of ferroptosis inhibitors with immunomodulators (e.g., anti-TIM-3, anti-IL-4Ra) may disrupt both

  generalfuture work
  Keywords: ferroptosis speci asthma immune metabolic cell airway epithelial role ferroptotic spatial critical mechanistic ammation axis
• Ferroptosis in smoke inhalation injury: from mechanisms to potential therapeutic targets (2026) · Frontiers in Cell and Developmental Biology · doi

  7.1 Repositioning ferroptosis within the SII injury network integrated contributor The current evidence supports ferroptosis as a biologically plausible and mechanistically to SII pathophysiology, particularly in the context of iron dysregulation after heme breakdown, lipid peroxidation induced by combustion- derived reactive species, and antioxidant depletion caused by toxic gas exposure. This interpretation must remain proportionate. SII is a multifactorial injury syndrome involving oxidative stress, innate immune activation, epithelial and endothelial damage, apoptosis, airway obstruction, vascular leakage, and fibrotic remodeling; ferroptosis does not replace these established mechanisms but intersects with them (Rehberg et al., 2009; Foncerrada et al., 2018). The available evidence, much of which derives from ALI, ARDS, COPD, hyperoxia, ischemia-reperfusion, and sepsis- associated models rather than SII-specific systems, does not justify describing ferroptosis as the dominant driver of SII. A more defensible interpretation is that ferroptosis functions as a redox-sensitive node within a broader network of regulated cell death and inflammatory amplification. Its clinical importance will likely depend on patient-specific variables, including iron burden, antioxidant reserve, inhaled toxicant profile, burn severity, infection risk, and timing of intervention (Yao et al., 2025a; Li J. et al., 2025).

  generalfuture work
  Keywords: ferroptosis within injury network evidence iron antioxidant interpretation specific repositioning integrated contributor current supports biologically
• Understanding the unique mechanism of ferroptosis: a promising therapeutic target (2024) · Frontiers in Cell and Developmental Biology · cited 39× · doi

  its for the used roles being agents clinical to lipid peroxidation of Since its discovery in 2012, ferroptosis has become a promising therapeutic target in cancer research. Several researchers are exploring and new and pathogenesis, therapy. are ferroptosis-inducing Ferroptosis is a novel mode of iron-dependent programmed cell death, which is induced by small molecules such as erastin and RSL3 (Table 2). The process is regulated by multiple metabolic pathways such as iron metabolism, GSH metabolism and lipid metabolism, and is accompanied by lethal ROS accumulation, which leads cell membrane. However, specific molecular markers for ferroptosis are not available, and the relevant mechanisms need to be further studied. This unique cell death pattern has generated numerous chemotherapeutic possibilities. However, the molecular mechanism of ferroptosis in cancer and its association with other diseases remains to be clarified. Several questions are unanswered in this context. For example, are there other pathways of ferroptosis regulation in addition to the classical pathway? Which is the main pathway that catalyzes the generation of lipid peroxides, any the nonenzymatic or mechanism of ferroptosis resistance? What are the molecular targets of ferroptosis-inducing therapy? How can ferroptosis- inducing antitumor drugs be used in clinical practice? Therefore, further research is required to comprehensively explore the mechanism of ferroptosis for eliminating aggressive tumors. enzymatic pathway? there

  generalfuture work
  Keywords: ferroptosis lipid inducing cell metabolism molecular mechanism pathway used clinical cancer several therapy iron death

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