Ferroptosis, a form of iron-dependent cell death driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated as a tumor-suppressor function for cancer therapy. Recent advance revealed that the sensitivity to ferroptosis is tightly linked to numerous biological processes, including metabolism of amino acid and the biosynthesis of glutathione. Here, by using a high-throughput CRISPR/Cas9-based genetic screen in HepG2 hepatocellular carcinoma cells to search for metabolic proteins inhibiting ferroptosis, we identified a branched-chain amino acid aminotransferase 2 (BCAT2) as a novel suppressor of ferroptosis. Mechanistically, ferroptosis inducers (erastin, sorafenib, and sulfasalazine) activated AMPK/SREBP1 signaling pathway through iron-dependent ferritinophagy, which in turn inhibited BCAT2 transcription. We further confirmed that BCAT2 as the key enzyme mediating the metabolism of sulfur amino acid, regulated intracellular glutamate level, whose activation by ectopic expression specifically antagonize system Xc^– inhibition and protected liver and pancreatic cancer cells from ferroptosis in vitro and in vivo. On the contrary, direct inhibition of BCAT2 by RNA interference, or indirect inhibition by blocking system Xc^– activity, triggers ferroptosis. Finally, our results demonstrate the synergistic effect of sorafenib and sulfasalazine in downregulating BCAT2 expression and dictating ferroptotic death, where BCAT2 can also be used to predict the responsiveness of cancer cells to ferroptosis-inducing therapies. Collectively, these findings identify a novel role of BCAT2 in ferroptosis, suggesting a potential therapeutic strategy for overcoming sorafenib resistance.

We present for the first time approaches to 3D-printing of nanocellulose hydrogel scaffolds based on double crosslinking, first by in situ Ca²⁺ crosslinking and post-printing by chemical crosslinking with 1,4-butanediol diglycidyl ether (BDDE). Scaffolds were successfully printed from 1% nanocellulose hydrogels, with their mechanical strength being tunable in the range of 3 to 8 kPa. Cell tests suggest that the 3D-printed and BDDE-crosslinked nanocellulose hydrogel scaffolds supported fibroblast cells’ proliferation, which was improving with increasing rigidity. These 3D-printed scaffolds render nanocellulose a new member of the family of promising support structures for crucial cellular processes during wound healing, regeneration and tissue repair.

Existing therapeutics for autoimmune diseases remain problematic due to low efficacy, severe side effects, and difficulties to reach target tissues. Herein, we design multifunctional fusion nanovesicles that can target lesions for the treatment of autoimmune skin diseases. The grapefruit‐derived exosome‐like nanovesicles (GEVs) with anti‐inflammatory and antioxidant effects are first encapsulated with CX5461, an immunosuppressant with anti‐proliferative properties to form GEV@CX5461. In order to enhance therapeutic efficiency and safety, GEV@CX5461 are then fused with CCR6+ nanovesicles derived from membranes of engineered gingiva‐derived mesenchymal stem cells (GMSCs). The resulting FV@CX5461 not only maintain the bioactivity of GEVs, CX5461, and GMSC membranes but also home to inflamed tissues rich in chemokine CCL20 through the chemotaxis function of CCR6 on FVs. Moreover, FV@CX5461 reduce the secretion of inflammatory factors, calm down Th17 cell activation, and induce Treg cell infiltration. Finally, impressive therapeutic efficiency in both psoriasis and atopic dermatitis disease models is demonstrated using FV@CX5461 to reshape the unbalanced immune microenvironment. A nanotherapeutic drug delivery strategy is developed using fusion nanovesicles derived from plant and animal cells with high clinical potential.

Excessive and persistent inflammation after injury lead to chronic wounds, increased tissue damage or even aggressive carcinogenic transformation. Effective wound repair could be achieved by inhibiting overactive immune cells to the injured site. In this study, we obtained high concentration of PD‐L1 in exosomes from either genetically engineered cells overexpressing PD‐L1 or IFN‐γ stimulated cells. We found that exosomal PD‐L1 is specially bound to PD‐1 on T cell surface, and suppressed T cell activation. Interestingly, exosomal PD‐L1 promoted the migration of epidermal cells and dermal fibroblasts when pre‐incubated with T cells. We further embedded exosomes into thermoresponsive PF‐127 hydrogel, which was gelatinized at body temperature to release exosomes to the surroundings in a sustained manner. Of importance, in a mouse skin excisional wound model, exosomal PD‐L1 significantly fastened wound contraction and reepithelialization when embedded in hydrogel during inflammation phase. Finally, exosomal PD‐L1 inhibited cytokine production of CD8+ T cells and suppressed CD8+ T cell numbers in spleen and peripheral lymph nodes. Taken together, these data provide evidence on exosomal PD‐L1 exerting immune inhibitory effects and promoting tissue repair.

Differentiated cancer cells reacquiring stem cell traits following radiotherapy may enrich cancer stem cells and accelerate tumor recurrence and metastasis. We are interested in the mechanistic role of dying cells-derived HMGB1 in CD133⁻ pancreatic cancer cells dedifferentiation following radiotherapy. We firstly confirmed that X-ray irradiation induced differentiation of CD133⁻ pancreatic cancer cells, from either sorted from patient samples or established cell lines, into cancer stem-like cells (iCSCs). Using an in vitro coculture model, X-ray irradiation induced dying cells to release HMGB1, which further promoted CD133⁻ pancreatic cancer cells regaining stem cell traits, such as higher sphere forming ability and expressed higher level of stemness-related genes and proteins. Inhibiting the expression and activity of HMGB1 attenuated the dedifferentiation stimulating effect of irradiated, dying cells on C133⁻ pancreatic cancer cells in vitro and in PDX models. Mechanistically, HMGB1 binding with TLR2 receptor functions in a paracrine manner to affect CD133⁻ pancreatic cancer cells dedifferentiation via activating Hippo-YAP pathway and HIF-1α expression in oxygen independent manner in vitro and in vivo. We conclude that X-ray irradiation induces CD133⁻ pancreatic cancer cell dedifferentiation into a CSC phenotype, and inhibiting HMGB1 may be a strategy to prevent CSC enrichment and further pancreatic carcinoma relapse.