Recent studies have suggested that exploring the potential mechanisms regulating ferroptosis vulnerability may contribute to improving the systemic therapeutic efficacy in HCC. High-density lipoprotein-binding protein (HDLBP), the largest RNA-binding protein, is an important transporter that protects cells from overaccumulation of cholesterol, but few studies have elucidated the role of HDLBP in the regulation of ferroptosis vulnerability in HCC. Our study suggests that HDLBP was markedly elevated in HCC compared with noncancerous liver tissues and that this elevation inhibited the ferroptosis vulnerability of HCC. Further experiments revealed that HDLBP bound to and stabilized the long noncoding RNA lncFAL (ferroptosis-associated lncRNA), which is derived from the plexin B2 gene. Moreover, our study suggests that the splicing of lncFAL was increased by YTH N6-methyladenosine (m6A) RNA-binding protein 2 (YTHDF2) in a m6A-dependent manner. Although HDLBP or lncFAL could not regulate the GPX4 antioxidant signalling pathway, lncFAL reduced ferroptosis vulnerability by directly binding to ferroptosis suppressor protein 1 (FSP1) and competitively abolishing Trim69-dependent FSP1 polyubiquitination degradation. More importantly, FSP1 inhibition promoted the antitumour activity of ferroptosis inducers both in vitro and in vivo. Collectively, our results provide a clinically promising demonstration that HDLBP stabilizes lncFAL, which mediates a FSP1-dependent anti-ferroptosis mechanism in HCC. These results support the enormous potential of disrupting FSP1 as a promising therapeutic approach for HCC patients with high HDLBP or lncFAL expression.

Adenosine monophosphate-activated protein kinase (AMPK) is a crucial energy sensor that maintains cellular energy homeostasis. AMPK plays a critical role in macroautophagy/autophagy, and autophagy facilitates hepatitis B virus (HBV) replication. To date, the intrinsic link among AMPK, autophagy and HBV production remains to be elucidated. Here, we demonstrate that PRKAA (a catalytic subunit of AMPK) is activated in response to HBV-induced oxidative stress, which in turn decreases the production of HBV. Mechanistic studies reveal that the autophagy machinery is associated with the inhibitory effect of PRKAA/AMPK on HBV production. Activation of PRKAA/AMPK promotes autolysosome-dependent degradation through stimulation of cellular ATP levels, which then leads to the depletion of autophagic vacuoles. Taken together, our data suggest that the activation of AMPK might be a stress response of host cells to restrict virus production through promotion of autophagic degradation. These findings therefore indicate that AMPK could provide a potential therapeutic target for HBV infection.

Recipients often suffer from hyperlactatemia during liver transplantation (LT), but whether hyperlactatemia exacerbates hepatic ischemia‐reperfusion injury (IRI) after donor liver implantation remains unclear. Here, the role of hyperlactatemia in hepatic IRI is explored. In this work, hyperlactatemia is found to exacerbate ferroptosis during hepatic IRI. Lactate‐primed lysine acetyltransferase 8 (KAT8) is determined to directly lactylate mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2) at Lys100 and augments PCK2 kinase activity. By using gene‐edited mice, evidence indicating that PCK2 exacerbates hepatic ferroptosis during IRI is generated. Mechanistically, PCK2 lactylate at Lys100 acts as a critical inducer of ferroptosis during IRI by competitively inhibiting the Parkin‐mediated polyubiquitination of 3‐oxoacyl‐ACP synthase (OXSM), thereby leading to metabolic remodeling of mitochondrial fatty acid synthesis (mtFAS) and the potentiation of oxidative phosphorylation and the tricarboxylic acid cycle. More importantly, targeting PCK2 is demonstrated to markedly ameliorate hyperlactatemia‐mediated ferroptosis during hepatic IRI. Collectively, the findings support the use of therapeutics targeting PCK2 to suppress hepatic ferroptosis and IRI in patients with hyperlactatemia during LT.

Recent studies suggest that circular RNA (circRNA)‐mediated post‐translational modification of RNA‐binding proteins (RBP) plays a pivotal role in metastasis of hepatocellular carcinoma (HCC). However, the specific mechanism and potential clinical therapeutic significance remain vague. This study attempts to profile the regulatory networks of circRNA and RBP using a multi‐omics approach. Has_circ_0006646 (circ0006646) is an unreported circRNA in HCC and is associated with a poor prognosis. Silencing of circ0006646 significantly hinders metastasis in vivo. Mechanistically, circ0006646 prevents the interaction between nucleolin (NCL) and the E3 ligase tripartite motif‐containing 21 to reduce the proteasome‐mediated degradation of NCL via K48‐linked polyubiquitylation. Furthermore, the change of NCL expression is proven to affect the phosphorylation levels of multiple proteins and inhibit p53 translation. Moreover, patient‐derived tumor xenograft and lentivirus injection, which is conducted to simulate clinical treatment confirmed the potential therapeutic value. Overall, this study describes the integrated multi‐omics landscape of circRNA‐mediated NCL ubiquitination degradation in HCC metastasis and provides a novel therapeutic target.