Epidermal growth factor receptor (EGFR), the receptor for members of the epidermal growth factor family, regulates cell proliferation and signal transduction; moreover, EGFR is related to the inhibition of tumor cell proliferation, angiogenesis, invasion, metastasis, and apoptosis. Therefore, EGFR has become an important target for the treatment of cancer, including non-small cell lung cancer, head and neck cancer, breast cancer, glioma, cervical cancer, and bladder cancer. First- to third-generation EGFR inhibitors have shown considerable efficacy and have significantly improved disease prognosis. However, most patients develop drug resistance after treatment. The challenge of overcoming intrinsic and acquired resistance in primary and recurrent cancer mediated by EGFR mutations is thus driving the search for alternative strategies in the design of new therapeutic agents. In view of resistance to third-generation inhibitors, understanding the intricate mechanisms of resistance will offer insight for the development of more advanced targeted therapies. In this review, we discuss the molecular mechanisms of resistance to third-generation EGFR inhibitors and review recent strategies for overcoming resistance, new challenges, and future development directions.

As a serine/threonine protein kinase, receptor-interacting protein 1 (RIP1) plays an important role in regulating the pathways in programmed cell death. Multifaceted human diseases (e.g., autoimmune diseases, inflammatory diseases, neurodegenerative diseases, and tumors) are closely related to RIP1 kinase. Therefore, small-molecule RIP1 inhibitors with precise targeting and good penetrability have recently been used in potentially therapeutic methods, attracting extensive researcher interest. GSK2982772, developed by GlaxoSmithKline (GSK), became the world’s first RIP1 inhibitor approved for clinical research in 2014. Nine clinical trials assessing GSK2982772 have been performed. The most recent direction in RIP1 inhibitor development has been focused on RIP1 small-molecule inhibitors with higher potency, selectivity, and metabolic stability. In this Perspective, considering the structure, biological functions, and disease relevance of RIP1, we summarize the recent research progress in RIP1 small-molecule inhibitor development based on different binding modalities and discuss prospective strategies for designing additional RIP1 therapeutic agents.

The preparation of the Nb coating was performed on the bare Ti–6Al–4V alloy using the double glow discharge plasma technique. It was characterized that the Nb coating exhibited a face centered cubic (fcc) crystal structure and a pronounced (200) preferred orientation. The SEM micrograph of the cross section for the coating displayed dense microstructure with a thickness of approximately 18 µm. The critical load (Lc) of the coating was determined to be about 83.5 N by the scratch tests. The electrochemical corrosion resistance of the coating was examined in Ringer’s solution at 37 °C by a series of electrochemical techniques, including open-circuit potential (OCP), potentiodynamic polarization, electrochemical impedance spectroscopy (EIS), and a Mott–Schottky analysis. As the result of the potentiodynamic polarization, the Nb coating possessed a more positive corrosion potential and lower corrosion current density than the Ti–6Al–4V substrate. EIS fitting date showed that the Nb coating always possessed a higher value of impedance and lower effective capacitance than those of the substrate during the five days of immersion testing. The main component of the passive film developed on the Nb coating was Nb2O5, confirmed by an X-ray photoelectron spectroscopy (XPS) analysis. A Mott–Schottky analysis demonstrated typical n-type semiconductor characteristics of the Nb coating, and both the donor density and flat band potential of the coating were lower than those of the substrate at all the given formation potential. These investigations demonstrate that the Nb coating can significantly improve the corrosion protection of uncoated Ti–6Al–4V and is thus a promising coating for the surface protection of bioimplants.

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Ferroptosis induced by detrimental accumulation of lipid peroxides has been recently linked to a variety of pathological conditions ranging from acute tissue injuries to chronic degenerative diseases and suppression of ferroptosis by small chemical inhibitors is beneficial to the prevention and treatment of these diseases. However, in vivo applicable small chemical ferroptosis inhibitors are limited currently. In this study, we screened an alkaloid natural compound library for compounds that can inhibit RSL3-induced ferroptosis in HT1080 cells and identified a group of bisbenzylisoquinoline (BBIQ) compounds as novel ferroptosis-specific inhibitors. These BBIQ compounds are structurally different from known ferroptosis inhibitors and they do not appear to regulate iron homeostasis or lipid ROS generation pathways, while they are able to scavenge 1,1-diphenyl-2-picryl-hydrazyl (DPPH) in cell-free reactions and prevent accumulation of lipid peroxides in living cells. These BBIQ compounds demonstrate good in vivo activities as they effectively protect mice from folic acid-induced renal tubular ferroptosis and acute kidney injury. Several BBIQ compounds are approved drugs in Japan and China for traditional uses and cepharanthine is currently in clinical trials against SARS-CoV-2, our discovery of BBIQs as in vivo applicable ferroptosis inhibitors will expand their usage to prevent ferroptotic tissue damages under various pathological conditions.