Abstract Lipophagy, a selective autophagic pathway, maintains lipid homeostasis and contributes to ferroptosis by supplying lipid peroxidation substrates. However, organic photosensitizers that activate lipophagy to promote ferroptosis remain scarce. Herein, we developed a NIR-II emissive photosensitizer (MBTTD) targeting lipid droplets (LDs). Compared with its analogue MBTTA, stronger electron-withdrawing groups bathochromically shifted absorption/emission and tuned excited-state decay, enabling efficient type I reactive oxygen species (ROS) generation and high photothermal conversion efficiency. MBTTD nanoparticles (NPs) localized to LDs upon cellular uptake. Upon 808 nm laser irradiation, MBTTD NP-mediated phototherapy disrupted LDs and induced Rab7-regulated lipophagy, releasing polyunsaturated fatty acids that underwent ROS-driven peroxidation, triggering extensive lipid peroxidation and ferroptosis. Concurrently, MBTTD-NP-mediated phototherapy triggered endoplasmic reticulum stress and apoptosis. MBTTD NPs showed favorable biocompatibility and potent therapeutic efficacy in multicellular tumor spheroids. In vivo studies revealed that MBTTD NPs enabled NIR-II imaging-guided phototherapy, suppressing 4T1 tumor growth without significant systemic toxicity.
Abstract Transcription factor EB (TFEB) is a promising target for autophagy regulation and cancer therapy, yet it has long been regarded as an undruggable protein. Starting from eltrombopag, an FDA-approved agent that exhibits both thrombopoietin receptor (Tpo-R) agonistic activity and TFEB inhibitory potency, we performed systematic structure−activity relationship optimization and identified DCL1191 as a potent, selective, and orally bioavailable TFEB inhibitor. DCL1191 binds TFEB with a Kd of 80.5 nM and disrupts the TFEB-DNA interaction with an IC50 of 60.5 nM. Computational modeling combined with site-directed mutagenesis elucidated its precise binding mode. DCL1191 exhibits diminished activity toward Tpo-R and MITF. Mechanistically, DCL1191 effectively represses the transcription of TFEB target genes and blocks intracellular autophagic flux. In autophagy-hyperactivated U87 glioblastoma cells, DCL1191 substantially sensitizes tumor cells to temozolomide chemotherapy. Pharmacokinetic evaluation in rats further demonstrated that DCL1191 possesses an i.v. half-life of 16.33 h and satisfactory oral bioavailability of 18.77%.
Abstract Local anesthetics (LAs), a type of substance with the ability of blocking nerve fiber conduction, are indispensable in clinical practice for pain relief. However, the duration of action and sensory-motor nerve selectivity of conventional LAs require further optimization. Herein, we wish to report the discovery of novel ammonium salts derived from natural cinchona alkaloids for long-acting and sensory-selective nerve blockades. The bicyclic quincoridine skeleton exhibited superior nerve blockade efficacy compared to acyclic and monocyclic analogs. Compound CLA-1-3 produced prolonged nerve blockade (over 50 h) in the rat sciatic nerve block model, possessing an IC50 value of approximately 0.39 μmol/L for voltage-gated sodium channel inhibition. On the other hand, at a concentration range of 0.30% to 0.60%, compound CLA-3-5 achieved sensory-selective nerve blockade lasting up to 3 h. The candidate molecules and underlying mechanistic insights will be valuable assets for drug development and therapeutic innovation.
Abstract Stimulator of interferon genes (STING) is a promising therapeutic target for severe acute pancreatitis (SAP), but effective small-molecule inhibitors remain limited. Here, structure−activity relationship studies identified compound D4 as a potent STING inhibitor with favorable cellular activity and safety. D4 directly engaged STING, inhibited its oligomerization and downstream TBK1/IRF3 signaling, and restored macrophage phagocytosis, autophagic flux, and mitochondrial function while suppressing NOD-like receptor family pyrin domain containing 3(NLRP3)-associated pyroptosis. D4 showed oral exposure with 24.70% bioavailability and no overt toxicity at 1000 mg/kg. In a caerulein/LPS-induced SAP model, D4 markedly reduced pancreatic injury, acinar cell necrosis, inflammatory infiltration, and serum amylase and lipase levels. STING knockdown produced similar protective effects. These findings identify D4 as a promising STING-targeting lead compound for SAP treatment.
Abstract Specifically disrupting lipid droplets (LDs) is an effective strategy for ablating tumor cells through photodynamic therapy (PDT). However, most reported LD probes possess short excitation/emission wavelengths, limiting tissue penetration, and LD-targeted theranostic probes remain underdeveloped. In this work, we first developed a family of near-infrared (NIR) charge-neutral and lipid droplet-targeting cyanine photosensitizers by systematically introducing heavy atoms (Br/I) at different sites of electrically neutral BF2-bridged cyanine (BCy5). These BCy photosensitizers retain the characteristic near-infrared absorption (>650 nm) and high molar extinction coefficients of classical cyanine dyes while exhibiting good singlet oxygen quantum yields. Notably, BCy5-Br1−BCy5-Br3 nanoparticles with high LD specificity exhibit significant PDT efficacy at submicromolar concentrations and, by inducing oxidative stress and lipid peroxidation (LPO) accumulation, concurrently trigger apoptosis and ferroptosis, effectively suppressing melanoma growth in vivo. This work provides vital insights into design principles and transformation of LD-targeting NIR cyanine photosensitizers for cancer PDT.
