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Cell death resistance is a hallmark of tumor cells that drives tumorigenesis and drug resistance. Targeting cell death resistance-related genes to sensitize tumor cells and decrease their cell death threshold has attracted attention as a potential antitumor therapeutic strategy. However, the underlying mechanism is not fully understood. Recent studies have reported that NeuroD1, first discovered as a neurodifferentiation factor, is upregulated in various tumor cells and plays a crucial role in tumorigenesis. However, its involvement in tumor cell death resistance remains unknown. Here, we found that NeuroD1 was highly expressed in hepatocellular carcinoma (HCC) cells and was associated with tumor cell death resistance. We revealed that NeuroD1 enhanced HCC cell resistance to ferroptosis, a type of cell death caused by aberrant redox homeostasis that induces lipid peroxide accumulation, leading to increased HCC cell viability. NeuroD1 binds to the promoter of glutathione peroxidase 4 (GPX4), a key reductant that suppresses ferroptosis by reducing lipid peroxide, and activates its transcriptional activity, resulting in decreased lipid peroxide and ferroptosis. Subsequently, we showed that NeuroD1/GPX4-mediated ferroptosis resistance was crucial for HCC cell tumorigenic potential. These findings not only identify NeuroD1 as a regulator of tumor cell ferroptosis resistance but also reveal a novel molecular mechanism underlying the oncogenic function of NeuroD1. Furthermore, our findings suggest the potential of targeting NeuroD1 in antitumor therapy.

Abstract Cancer stem cells (CSCs) are associated with tumor progression, recurrence, and therapeutic resistance. To maintain their pool while promoting tumorigenesis, CSCs divide asymmetrically, producing a CSC and a highly proliferative, more differentiated transit‐amplifying cell. Exhausting the CSC pool has been proposed as an effective antitumor strategy; however, the mechanism underlying CSC division remains poorly understood, thereby largely limiting its clinical application. Here, through cross‐omics analysis, yin yang 2 (YY2) is identified as a novel negative regulator of CSC maintenance. It is shown that YY2 is downregulated in stem‐like tumor spheres formed by hepatocarcinoma cells and in liver cancer, in which its expression is negatively correlated with disease progression and poor prognosis. Furthermore, it is revealed that YY2 overexpression suppressed liver CSC asymmetric division, leading to depletion of the CSC pool and decreased tumor‐initiating capacity. Meanwhile, YY2 knock‐out in stem‐like tumor spheres caused enrichment in mitochondrial functions. Mechanistically, it is revealed that YY2 impaired mitochondrial fission, and consequently, liver CSC asymmetric division, by suppressing the transcription of dynamin‐related protein 1. These results unravel a novel regulatory mechanism of mitochondrial dynamic‐mediated CSCs asymmetric division and highlight the role of YY2 as a tumor suppressor and a therapeutic target in antitumor treatment.

Background Sorafenib is mainly used to treat patients with hepatocellular carcinoma (HCC) Barcelona Clinic Liver Cancer (BCLC) stage C, many of whom also have severe cirrhosis. However, hypersplenism and digestive tract hemorrhage are common complications of cirrhosis, which increase the risk and difficulty of treatment. Methods Nineteen patients with HCC BCLC stage C with hypersplenism were treated with sorafenib plus partial splenic embolism at Chongqing University Cancer Hospital, Chongqing, China, between January 2015 and June 2018. We analyzed the therapeutic effect and clinical safety of this treatment in these patients. Result Hypersplenism was rectified in all patients. The incidence rates of hemorrhage and myelosuppression were 0%, and the mean survival time was 11.2 months. Conclusion Sorafenib plus partial splenic embolism could relieve hypersplenism and prolong survival in patients with BCLC stage C HCC.

Hepatic splenosis is an uncommon condition that occurs following traumatic splenic rupture or splenectomy. The case of a 41-year-old male patient with multiple isolated liver masses indistinguishable from primary and metastatic liver tumours is reported. Following laparotomy, the liver lesions were resected and histopathology confirmed a diagnosis of hepatic splenosis. At an 18-month follow-up examination, no abnormalities in routine blood test, liver function, and liver computed tomography (CT) scanning were observed. After review of the literature, the following diagnostic criteria for hepatic splenosis are proposed: (1) a history of splenic trauma or splenectomy; (2) lesion(s) with a surrounding rim, particularly near the liver capsule identified by CT scanning; (3) findings on superparamagnetic iron oxide-enhanced magnetic resonance imaging or technetium-99m heat-damaged red cell scanning; and (4) histopathological findings (needle biopsy or surgical pathology). The following diagnostic process is also proposed: suspect diagnosis when criteria 1 and 2 are met; make diagnosis when criterion 3 is met; confirm diagnosis when criterion 4 is met. Laparotomy is recommended for either diagnosis or treatment when invasive procedures are necessary.