Ferritinophagy, a selective autophagic process mediated by nuclear receptor coactivator 4 (NCOA4), plays a central role in maintaining cellular iron homeostasis by degrading ferritin and releasing stored iron. Under physiological conditions, this process dynamically regulates iron storage and utilization, thereby preventing both iron deficiency and iron overload. However, under pathological conditions such as chronic inflammation, oxidative stress, and harmful environmental exposures, aberrant activation of ferritinophagy leads to excessive ferritin degradation and abnormal expansion of the cytosolic labile iron pool. This, in turn, drives the accumulation of iron-dependent reactive oxygen species and lipid peroxidation, lowering the threshold for ferroptosis initiation, exacerbating tissue injury, and promoting disease progression. Thus, the pathological significance of ferritinophagy lies not only in iron mobilization itself but also in its close coupling with ferroptosis. This “ferritinophagy–ferroptosis axis” has emerged as a key framework for understanding the link between iron dysregulation and disease pathogenesis. In recent years, increasing evidence has shown that this axis is repeatedly activated in various chronic respiratory diseases (CRDs), where it exerts a pivotal role in disease onset and progression. This review systematically summarizes the molecular mechanisms of NCOA4-mediated ferritinophagy and highlights the potential pathogenic role of the ferritinophagy–ferroptosis axis in different CRDs, aiming to provide a theoretical basis for identifying novel therapeutic strategies and intervention targets. Graphical Abstract 1. Ferritinophagy controls intracellular iron release and shapes ferroptosis susceptibility in lung cells. 2. The ferritinophagy–ferroptosis axis shows strong disease- and cell-type specificity across chronic respiratory diseases (CRDs) 3. Targeting iron mobilization pathways may offer new therapeutic strategies for CRDs

Objective: To identify factors associated with severe Pneumocystis jirovecii pneumonia (PJP) and in-hospital mortality and evaluate their ability to discriminate severe PJP in children without human immunodeficiency virus (HIV) infection. Methods: This single-center retrospective cohort study included 61 children with non-HIV-associated PJP admitted between February 2022 and June 2025, including 31 with non-severe and 30 with severe PJP. Univariable and multivariable Firth penalized logistic regression identified factors associated with severe PJP, and receiver operating characteristic curves assessed discrimination. A restricted Firth logistic model explored in-hospital mortality among severe cases. Results: Thirty children (49.2%) had severe PJP, and nine (14.8%) died during hospitalization; all deaths occurred in the severe group. Compared with the non-severe group, the severe group had more frequent primary immunodeficiency, fever, dyspnea, and cytomegalovirus (CMV) coinfection; higher D-dimer, lactate dehydrogenase (LDH), procalcitonin, and CT severity scores; and lower albumin, PaO ₂ /FiO ₂ , and CD4 ⁺ /CD8 ⁺ T-cell ratios (all P<0.05). In the primary multivariable model, LDH (per 100-U/L increase: adjusted odds ratio [aOR]=1.532, 95% confidence interval [CI]: 1.061–2.374; P = 0.021) and CMV coinfection (aOR=5.164, 95% CI: 1.099–28.048; P = 0.037) were associated with severe PJP. LDH remained significant in the sensitivity analysis, whereas CMV coinfection did not. LDH discriminated severe from non-severe PJP with an area under the curve of 0.868 (95% CI: 0.776–0.960); the optimal cutoff was 423.0 U/L, with 90.0% sensitivity and 71.0% specificity. The combined model had an AUC of 0.878 (95% CI: 0.791–0.966), without significant improvement over LDH alone (P = 0.701). Among severe cases, non-survivors had more frequent malnutrition and CMV coinfection, higher LDH and procalcitonin, and lower neutrophil counts, albumin, PaO ₂ /FiO ₂ , and CD4 ⁺ /CD8 ⁺ T-cell ratios (all P<0.05). In the exploratory mortality model, LDH (per 100-U/L increase: aOR=1.654, 95% CI: 1.080–4.271; P = 0.018) and albumin (per 1-g/L increase: aOR=0.605, 95% CI: 0.251–0.878; P = 0.004) were associated with in-hospital mortality. Conclusions: Elevated LDH was consistently associated with severe PJP and showed good discrimination. CMV coinfection was associated with severe PJP only in the primary model and provided no significant incremental discrimination. Elevated LDH and decreased albumin may be associated with in-hospital mortality. Larger external cohorts are needed to validate these findings.

Juvenile sepsis-associated brain injury (SABI) lacks effective targeted therapies, and ferroptosis has emerged as a critical pathogenic mechanism. N⁶-methyladenosine (m⁶A) modification is increasingly recognized as a key epitranscriptomic regulator in inflammatory and neurological disorders, yet its role in ferroptosis regulation during SABI remains unexplored. Here, we identify a novel METTL3–PCBP1–ferroptosis axis that drives hippocampal neuronal injury in SABI. Using a cecal ligation and puncture (CLP)-induced rat SABI model and an in vitro co-culture system of lipopolysaccharide (LPS)-stimulated microglia with primary hippocampal neurons, we demonstrate that SABI significantly upregulates methyltransferase-like 3 (METTL3) expression and global m⁶A modification levels in the hippocampus. MeRIP-seq reveals that poly(rC)-binding protein 1 (Pcbp1) mRNA—encoding an iron chaperone that maintains cellular iron homeostasis—exhibits the most pronounced increase in m⁶A modification among cell death-related genes, with site-specific methylation at position 1151 (GGACA motif). This modification recruits the m⁶A reader YTH domain-containing family protein 2 (YTHDF2), promoting Pcbp1 mRNA decay and subsequent PCBP1 protein downregulation. Loss of PCBP1 reduces glutathione peroxidase 4 (GPX4) expression—likely through impaired mRNA binding—and disrupts intracellular Fe²⁺ homeostasis, ultimately triggering ferroptosis characterized by lipid peroxidation and mitochondrial damage. Notably, METTL3 knockdown restores PCBP1 expression, normalizes Fe²⁺ levels, upregulates GPX4, and attenuates ferroptosis and hippocampal injury; however, concurrent PCBP1 knockdown reverses these protective effects. Furthermore, PCBP1 overexpression in SABI rats rescues ferroptosis and neurological deficits. Collectively, our findings establish that METTL3-mediated m⁶A modification of Pcbp1 mRNA exacerbates ferroptosis and SABI pathogenesis, identifying the METTL3/PCBP1 axis as a promising therapeutic target for juvenile SABI.