Biology subjects

Lee, Z.

Publications and source records attributed to Lee, Z..

4 recordsLinked to original sources

bioRxiv2026

Self-severing circuits facilitate passage of ingestible electronic sensor-guided therapeutics

Ingestible electronics enable the tracking and treatment of gastrointestinal and systemic diseases. However, bulky batteries and circuit boards require large capsules that can result in bowel obstruction, a medical emergency. Here, we engineered a 9 x 26 mm electronic pill capable of triggered severing into tiny pieces with sizes clinically proven to reduce obstruction risk. Our capsule enables multicomponent circuit boards to connect with separately encapsulated powering elements via conductive, interlocking connections. Heat induced softening of polyethylene glycol/polycaprolactone channels activates a spring to separate encapsulated components into inert 9 x 15 mm segments, facilitating intestinal passage. Separation triggers included closed-loop sensors and time-delay circuits. In vivo swine studies demonstrate the ability of our capsules to sense luminal oxygen changes via an optoelectronic sensor, locally trigger upadacitinib delivery, and facilitate safe excretion.

bioengineering↗

bioRxiv2025

The Lipid Hydrolase ABHD6 is a Therapeutic Target in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)-Related Hepatocellular Carcinoma

Primary liver cancer accounts for approximately 700,000 deaths worldwide annually ranking third in cancer-related mortality, with hepatocellular carcinoma (HCC) comprising the majority of these tumors. Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently a leading cause of HCC in the United States. We previously identified the lipid hydrolase alpha/beta hydrolase domain 6 (ABHD6) as a key mediator of the development of metabolic syndrome and intimately involved in cell signaling, making it a prime target for investigation in MASLD-related HCC. ABHD6 displays higher expression within HCC tumor cores when compared to adjacent non-tumor liver tissue in human subjects. Using an in vivo antisense oligonucleotide (ASO)-driven knockdown approach, we have shown the inhibition of ABHD6 prevents the development and progression of HCC in an obesity/MASLD-driven mouse model. Additionally, a xenograft model using the human Huh7 cell line displayed reduced tumor engraftment and growth with ABHD6 genetic deletion and small molecule inhibition. ABHD6 knockout cells demonstrated increased levels of bis(monoacylglycerol)phosphates (BMPs), lipids relevant to high fat diet-induced lysosomal dysfunction, and knockout cells also demonstrated altered autophagy and lysosomal activity using in vitro model of saturated fatty acid-induced lipotoxicity. These studies reveal novel lipid signaling mechanisms by which MASLD progresses towards HCC and provide support for ABHD6 as a therapeutic target in HCC. SignificanceWe have identified that alpha/beta hydrolase domain 6 (ABHD6) plays a role in lysosomal membrane lipid remodeling pathways that are relevant in obesity/MASLD-driven HCC. Inhibitors targeting ABHD6 reorganize lysosomal lipid homeostasis to improve outcomes in HCC.

cancer biology↗

bioRxiv2025

Labile iron pool dynamics do not drive ferroptosis potentiation in colorectal cancer cells

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. CRC tumors exhibit aberrant iron accumulation, which supports tumor cell proliferation through multiple metabolic pathways. However, the oncogenic benefits of elevated iron must be counterbalanced by its potential to catalyze oxidative damage via reactive oxygen species generated from labile, redox-active iron. Ferroptosis is a regulated, non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation. This process is tightly controlled by the selenoenzyme glutathione peroxidase 4 (GPX4), which reduces lipid peroxides and can be pharmacologically inhibited by agents such as RSL3 and JKE1674. A key source of redox-active iron is the labile iron pool (LIP), yet its role in regulating ferroptosis remains incompletely defined. To examine this, we supplemented CRC cells with exogenous iron following pharmacologic induction of ferroptosis. Iron supplementation significantly reduced cell viability, suggesting that expansion of the LIP potentiates ferroptotic cell death. However, whether ferroptosis is accompanied by dynamic changes in the LIP, and if such changes are mechanistically required for its potentiation, were unknown. To further characterize this response, we profiled the expression of iron regulatory genes under ferroptotic conditions and observed no change in transcriptional response in iron homeostasis genes. Using a reactivity-based probe of labile iron, we found that the LIP did not measurably increase during ferroptosis induction with GPX4 inhibition or inhibition of the SLC7A11 cysteine/glutamate antiporter. These findings suggest that the LIP does not expand upon pharmacological initiated ferroptosis, despite the potentiating effect of exogenous iron supplementation.

cancer biology↗

bioRxiv2024

Skeletal Metastasis of Prostate Cancer Is Augmented by Activation of EphA2 Noncanonical Signaling and Ligand-Deficient Bone Microenvironment

EphA2, a member of Eph family receptor tyrosine kinases (RTKs), is overexpressed in multiple types of solid human tumors, particularly at the late stages. However, whether and how it drives specific malignant processes remain elusive. We report that EphA2 is elevated during prostate cancer (PCa) progression in multiple syngeneic murine models. Interestingly, human metastatic PCa specimens from two Rapid Autopsy Programs showed selective overexpression of EphA2 in metastasis to the bone, but not to the lymph nodes or viscera. Serine 897 phosphorylation that mediates the pro-oncogenic, noncanonical signaling by EphA2 was also upregulated in bone metastasis. Analysis of human datasets shows EphA2 overexpression is associated with skeletal but not visceral metastases. Ephrin-A1, a major cognate ligand for EphA2, is lost in PCa bone metastasis, which is correlated with poor prognosis. Further, the bone microenvironment is unique in expressing little of the five EFNA genes, providing permissive microenvironment for bone colonization. S897A mutation that ablates EphA2 noncanonical signaling, suppressed PCa development. Restoration of ephrin-A1 expression in PC-3, a model cell line for double negative prostate cancer derived from bone metastasis and devoid of ephrin-As, profoundly changed global tyrosine phosphorylation profiles, inhibited basal ERK and Src activities in vitro, and suppressed tumor development in the bone. Together these results demonstrate EphA2 overexpression and concomitant loss of ligands in PCa lead to activation of noncanonical signaling that is sustained in ephrin-A1-deficient skeletal milieu to promote bone metastasis.

cancer biology↗