AKR1C3-dependent lipid droplet formation confers hepatocellular carcinoma cell adaptability to targeted therapy.

Rationale: Increased lipid droplet (LD) formation has been linked to tumor metastasis, stemness, and chemoresistance in various types of cancer. Here, we revealed that LD formation is critical for the adaptation to sorafenib in hepatocellular carcinoma (HCC) cells. We aim to investigate the LD function and its regulatory mechanisms in HCC. Methods: The key proteins responsible for LD formation were screened by both metabolomics and proteomics in sorafenib-resistant HCC cells and further validated by immunoblotting and immunofluorescence staining. Biological function of AKR1C3 was evaluated by CRISPR/Cas9-based gene editing. Isotopic tracing analysis with deuterium3-labeled palmitate or carbon13-labeled glucose was conducted to investigate fatty acid (FA) and glucose carbon flux. Seahorse analysis was performed to assess the glycolytic flux and mitochondrial function. Selective AKR1C3 inhibitors were used to evaluate the effect of AKR1C3 inhibition on HCC tumor growth and induction of autophagy. Results: We found that long-term sorafenib treatment impairs fatty acid oxidation (FAO), leading to LD accumulation in HCC cells. Using multi-omics analysis in cultured HCC cells, we identified that aldo-keto reductase AKR1C3 is responsible for LD accumulation in HCC. Genetic loss of AKR1C3 fully depletes LD contents, navigating FA flux to phospholipids, sphingolipids, and mitochondria. Furthermore, we found that AKR1C3-dependent LD accumulation is required for mitigating sorafenib-induced mitochondrial lipotoxicity and dysfunction. Pharmacologic inhibition of AKR1C3 activity instantly induces autophagy-dependent LD catabolism, resulting in mitochondrial fission and apoptosis in sorafenib-resistant HCC clones. Notably, manipulation of AKR1C3 expression is sufficient to drive the metabolic switch between FAO and glycolysis. Conclusions: Our findings revealed that AKR1C3-dependent LD formation is critical for the adaptation to sorafenib in HCC through regulating lipid and energy homeostasis. AKR1C3-dependent LD accumulation protects HCC cells from sorafenib-induced mitochondrial lipotoxicity by regulating lipophagy. Targeting AKR1C3 might be a promising therapeutic strategy for HCC tumors.

The Effect of Mindful Leadership on Employee Innovative Behavior: Evidence from the Healthcare Sectors in China.

In the health care system, it is increasingly apparent that employee innovative behavior improves the core competitiveness and resilience of organizations. Previous research has identified leadership behavior as a key predictor of employee innovative behavior. Following this logic and by integrating social information processing theory with existing research conclusions, we constructed a moderated mediation model to examine the mechanism by which mindful leadership influences employee innovative behavior. An empirical analysis of 361 questionnaires that were completed by employees from the healthcare sector in China shows that mindful leadership is positively and significantly correlated with employee innovative behavior. Creative process engagement was found to play a mediating role in this relationship. Moreover, creative self-efficacy positively moderated the relationship between mindful leadership and creative process engagement and moderated the mediating effect of creative process engagement on the relationship between mindful leadership and employee innovative behavior. That is, compared with employees with lower creative self-efficacy, employees with higher creative self-efficacy experienced a stronger indirect effect of mindful leadership on their innovative behavior. This study enriches the theoretical research on mindful leadership, clarifies the mechanism and boundary conditions of the effect of mindful leadership on employee innovative behavior, and provides theoretical support for organizational activities that stimulate and guide employee innovative behavior.