Ying Xin

Angiotensin II (Ang II)-mediated oxidative stress is the key pathological driver of cardiomyopathy, yet the gut microbiota-dependent regulatory network underlying this process remains unclear. Administration of a sub-pressor dose of Ang II to C57BL/6 J mice induced cardiac oxidative stress and dysfunction via signal transducer and activator of transcription 1 (STAT1)-triggered upregulation of indoleamine 2,3-dioxygenase 1 (IDO1), which promoted angiopoietin like protein 4 (ANGPTL4) and gp91 phox-driven oxidative damage; IDO1 pharmacological reduction partially reversed these effects. Mechanistically, IDO1 induced ANGPTL4 by relieving Notch1/HES1 transcriptional repression, independently of its catalytic activity: Y111 phosphorylation of IDO1 recruited SHP2 to suppress Notch1/HES1 signaling, revealing a previously unrecognized, non-enzymatic function. Concurrently, Ang Ⅱ depleted gut microbiota-derived butyrate, contributing to cardiomyopathy through the same STAT1/IDO1 axis, while cardiac-specific overexpression of Ido1 attenuated butyrate’s protective effect. Furthermore, butyrate also suppressed IDO1 by enhancing H3K9 acetylation-mediated AHR/SOCS3 activation and promoting IDO1 ubiquitin-proteasomal degradation. These findings identify a gut-heart signaling circuit in which gut microbiota-derived butyrate modulates IDO1 expression and its non-enzymatic pro-oxidative function, positioning the butyrate/IDO1/ANGPTL4 axis as a potential therapeutic target for oxidative stress and Ang II-associated cardiomyopathy.

Abnormal iron metabolism and ferroptosis contribute to diabetic cardiomyopathy (DCM); however, the regulatory mechanisms remain unclear. Inulin improves systemic metabolism and cardiac function, but whether it alleviates myocardial ferroptosis and DCM is unknown. Using two distinct type 2 diabetes (T2D) mouse models—the high-fat diet combined with streptozotocin–induced T2D model and the db/db mouse model—in combination with an iron chelator, we found that imbalanced iron homeostasis and ferroptosis drive DCM. Inulin restored cardiac iron homeostasis, inhibited ferroptosis and DCM, and promoted short-chain fatty acids (SCFAs). Treatment with an SCFA inhibitor confirmed that SCFAs mediate the cardioprotective effects of inulin, with butyrate exerting the most potent antiferroptotic effect. Hypoxia-inducible factor 1α (HIF-1α) expression was decreased in DCM, and bioinformatic analysis identified HIF-1α as a hub gene in ferroptosis. Interference with HIF-1α in the two distinct T2D mouse models and in vitro weakened the antiferroptotic effect of butyrate. Mechanistically, butyrate inhibited HIF-1α ubiquitination by inducing HIF-1α butyrylation at lysine 190, which upregulated transcription of ferritin heavy chain (FTH) and mitochondrial ferritin (FTMT) to enhance the storage of unstable iron. HIF-1α acts as a critical regulator of myocardial iron homeostasis through transcriptional upregulation of FTH/FTMT. Inulin-fermented butyrate prevents ferroptosis-driven DCM, and its protective effect depends on the HIF-1α–FTH/FTMT axis via butyrylation. These findings highlight the therapeutic potential of using inulin or targeting HIF-1α in the management of DCM and diseases associated with aberrant iron metabolism. Article Highlights: Dysregulated iron metabolism and ferroptosis contribute to diabetic cardiomyopathy (DCM); however, the regulatory mechanisms and effective therapeutic strategies remain elusive. We sought to identify the role of hypoxia-inducible factor 1α (HIF-1α) in regulating myocardial iron homeostasis and ferroptosis in DCM, as well as evaluate the preventive effects of inulin on ferroptosis-induced DCM and elucidate its mechanism. Inulin-fermented butyrate activates the HIF-1α–ferritin heavy chain (FTH)/mitochondrial ferritin (FTMT) axis, alleviating cardiac ferroptosis and DCM, and stabilizes HIF-1α by promoting K190 Kbu modification and inhibiting ubiquitin-dependent degradation. Targeting the HIF-1α–FTH/FTMT axis via inulin, butyrate, or alternative approaches may represent a promising therapeutic strategy for alleviating DCM and other diabetes complications.

Angiotensin II (AngII) activation, a key driver of diabetes pathogenesis and associated complications, induces kidney injury by promoting oxidative stress and inflammation. Ferroptosis is an iron-dependent regulated cell death, playing a crucial role in kidney injury. This study aimed to explore the contribution of ferroptosis to AngII-induced kidney injury and its regulatory mechanisms. Our findings reveal that chronic AngII stimulation leads to renal dysfunction, characterized by elevated serum creatinine levels, increased urinary protein-to-creatinine ratio, and tubular injury. These changes are associated with ferroptosis in renal tubular epithelial cells (TECs) and a marked upregulation of dipeptidase 1 (DPEP1) expression. Notably, the ferroptosis inhibitor ferrostatin-1 (Fer-1) effectively reversed ferroptosis in TECs, restored tubular integrity, and improved renal function. DPEP1 gene silencing and the DPEP1 inhibitor cilastatin significantly inhibited AngII-induced ferroptosis in TECs. Mechanistically, AngII upregulated DPEP1 expression via the transcription factor SP1. Elevated DPEP1 enhanced ubiquitination of SLC3A2, a key cystine/glutathione transporter. Furthermore, inhibiting DPEP1 with cilastatin in a mouse model effectively reversed ferroptosis and alleviated kidney injury. These findings highlight ferroptosis’ key role in AngII-induced kidney injury and suggest DPEP1 targeting as a therapeutic strategy against AngII-driven renal damage. Article Highlights: This study investigated the role of ferroptosis in angiotensin II (AngII)-induced kidney injury, addressing a critical gap in understanding AngII-mediated nephropathy mechanisms. We asked whether dipeptidase 1 (DPEP1)-mediated SLC3A2 degradation drives ferroptosis and renal damage under AngII activation. AngII upregulates DPEP1 via SP1, promoting SLC3A2 ubiquitination and glutathione depletion, ultimately triggering tubular ferroptosis. DPEP1 inhibition rescues renal function. Targeting the SP1-DPEP1-SLC3A2 axis offers a novel therapeutic strategy against ferroptosis-dependent kidney injury in hypertension and metabolic disorders.

Background and Aims: Portal vein tumor thrombus (PVTT) occurs frequently in hepatocellular carcinoma (HCC) patients. However, there is currently no satisfactory treatment. Radiotherapy (RT) and tyrosine kinase inhibitors (TKI) are currently commonly used. However, whether their combined use provides a survival benefit is debatable. This retrospective study compared the efficacy and safety between radiotherapy plus lenvatinib (RT + L) and radiotherapy plus sorafenib (RT + S) in the treatment of hepatocellular carcinoma with portal vein tumor thrombus (PVTT).Methods: Among patients with PVTT who received RT + L or RT + S between March 2017 and September 2022, the primary endpoints were overall survival (OS) and progression-free survival (PFS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), and incidence of treatment-related adverse effects. The prognostic factors were also assessed.Results: The analysis included 152 patients (RT + L: 48; RL: 25; RT + S: 55; S: 24). Compared with the RT + S group, the RT + L group had a longer OS and PFS. Among patients with type I/II PVTT, the median OS times were 19.8 months and 13.5 months (p = 0.047) and the median PFS was 12.3 months and 7.3 months (p = 0.042), respectively. And the median OS of the patients with type I/II PVTT were 14.4 months and 8.3 months (p = 0.030) and the median PFS was 8.3 months and 6.2 months (p = 0.026). ORR and DCR in RT + L group (25.0% and 75.0%) were also little higher than those in RT + S group (20.0% and 70.9%), but not statistically significant. In univariate analysis, etiology, Type of PVTT, alpha-fetoprotein (AFP) level, Child–Pugh score, and treatment method influenced OS. Multivariate analysis confirmed that treatment method, etiology, alpha-fetoprotein (AFP) level, and Child–Pugh score were independent prognostic factors for OS. Similar safety profiles were observed in the RT + L and RT + S groups. The most common adverse events were myelosuppression, decreased liver function, fatigue, diarrhea, nausea, and vomiting. Most adverse reactions were grade 1–2.Conclusion: The side effects of radiotherapy plus lenvatinib were acceptable. Compared to RT + S, RT + L had good efficacy in the treatment of hepatocellular carcinoma with PVTT. Validation is needed in prospective studies with larger sample sizes.