Haodang Luo

Ferroptosis is a form of programmed cell death characterized by iron‐dependent phospholipid peroxidation and is implicated in a wide range of human diseases. Emerging evidence highlights the critical role of epigenetic regulation in this process. Dysregulation of histone post‐translational modifications (HPTMs) is increasingly recognized as a pivotal mechanism linking metabolic reprogramming to various pathological conditions. HPTMs constitute one of the key epigenetic regulatory mechanisms and mediate ferroptosis by modulating the transcription of core ferroptosis‐related genes. This review systematically summarizes site‐specific HPTMs, including histone methylation, acetylation, ubiquitination, phosphorylation, lactylation, and β‐hydroxybutyrylation. Furthermore, we elucidate how infectious diseases, tumors, and chronic non‐infectious conditions drive disease progression via HPTMs‐dependent regulation of ferroptosis. A comprehensive dissection of these epigenetic regulatory networks may facilitate the development of combinatorial therapeutic strategies targeting HPTMs and ferroptosis inducers, thereby providing new insights into the treatment of ferroptosis‐associated disorders.

Bartonella henselae establishes persistent infections by manipulating host cell survival, but mechanisms beyond the known type IV secretion system (T4SS)-cAMP pathway are poorly understood. Here, we delineate a novel anti-apoptotic axis in human endothelial cells hijacked by B. henselae. We found that infection upregulates the pro-survival factor amphiregulin (AREG). This induction is initiated by the intracellular sensor NOD2, which triggers a PI3K/AKT/CREB signaling cascade, culminating in CREB-dependent transcription of AREG. Functional studies confirmed that secreted AREG acts via its receptor, EGFR, to suppress apoptosis, establishing a complete NOD2-AREG-EGFR autocrine loop. Collectively, our findings characterize a sophisticated survival strategy where B. henselae links intracellular innate immune sensing to the activation of an autocrine growth factor loop. The delineation of this novel NOD2-AREG-EGFR axis reveals a parallel mechanism of host cell manipulation, adding a new layer of complexity to our understanding of Bartonella–host interactions.

Airway epithelial cells play a pivotal role in the early host response to Mycoplasma pneumoniae colonization. Our previous study has revealed that M. pneumoniae infection induces metabolic reprogramming in bronchial epithelial cells. However, the mechanisms underlying these metabolic shifts and their contribution to the pathogenesis of pneumonia remain unclear. Herein, we demonstrate that M. pneumoniae infection activates signal transducer and activator of transcription 3 (STAT3), which drives citrate accumulation in airway epithelial cells. Citrate is metabolized by adenosine triphosphate-citrate lyase (ACLY) into acetyl coenzyme A, which is further converted to malonyl coenzyme A, promoting post-translational modifications such as histone acetylation and glyceraldehyde-3-phosphate dehydrogenase malonylation (GAPDH). In vivo, pharmacological inhibition of STAT3 or ACLY attenuated pulmonary inflammation and pro-inflammatory cytokine expression yet paradoxically delayed pathogen clearance, as evidenced by increased colonyforming units in bronchoalveolar lavage fluid and lung tissue. These findings demonstrate that targeting the STAT3/ACLY axis exerts antiinflammatory potential without direct antibacterial activity. Our work highlights the dual regulatory roles of citrate metabolism in inflammation and pathogen control and suggests that combined use of STAT3/ACLY inhibitors with conventional antibiotics may be necessary to achieve both immunomodulation and effective bacterial eradication.

Peripheral tolerance of T cells is necessary because thymic deletion is not complete, and tissue-specific Ags exist outside the thymus. We have reported that persistent Ag is required to maintain peripheral tolerance in vivo. We suspect that the TCR signaling pathway in in vivo tolerized cells is compromised due to continuous exposure to the Ags. In this study, the TCR signaling events in these cells were investigated using TCR transgenic mice (2C mice) whose T cells are predominantly Ld alloantigen-specific CD8 cells. The 2C mice were thymectomized and then rendered tolerant to Ld Ag by allogenic heart transplantation plus short-term treatment with rapamycin. We found that 1) the in vivo tolerized CD8 cells have compromised intracellular Ca2+ flux upon mitogen stimulation; and 2) their cellular tyrosine proteins fail to be phosphorylated properly upon TCR cross-linking. These results indicate that the signaling pathway in the in vivo tolerized CD8 cells is indeed defective. We also found that 1) the tolerized CD8 cells have no characteristic surface markers; and 2) the allograft is probably the place where the rejection response is initiated according to the appearance of an early activation marker of T cells on graft-infiltrating cells.