Natural products have been a bedrock for drug discovery for decades. (−)-Epigallocatechin-3-gallate (EGCG) is one of the widely studied natural polyphenolic compounds derived from green tea. It is the key component believed to be responsible for the medicinal value of green tea. Significant studies implemented in in vitro, in cellulo, and in vivo models have suggested its anti-oxidant, anti-cancer, anti-diabetic, anti-inflammatory, anti-microbial, neuroprotective activities etc. Despite having such a wide array of therapeutic potential and promising results in preclinical studies, its applicability to humans has encountered with rather limited success largely due to the poor bioavailability, poor membrane permeability, rapid metabolic clearance and lack of stability of EGCG. Therefore, novel techniques are warranted to address those limitations so that EGCG or its modified analogs can be used in the clinical setup. This review comprehensively covers different strategies such as structural modifications, nano-carriers as efficient drug delivery systems, synergistic studies with other bioactivities to improve the chemico-biological aspects (e.g., stability, bioavailability, permeability, etc.) of EGCG for its enhanced pharmacokinetics and pharmacological properties, eventually enhancing its therapeutic potentials. We think this review article will serve as a strong platform with comprehensive literature on the development of novel techniques to improve the bioavailability of EGCG so that it can be translated to the clinical applications.

Autophagy and paraptosis are two distinct physiological mechanisms involved in regulating cell fate in cancer. Recent studies have demonstrated that autophagy is a crucial process for maintaining cellular homeostasis by facilitating the removal of misfolded proteins and damaged organelles. However, autophagy is found to play a dual role in cancer. Severe ER and mitochondrial dysfunction can trigger different forms of programmed cell death, including autophagic cell death. In cancer cells that evade apoptosis, paraptosis, a caspase-independent alternate death pathway, is triggered by ER and mitochondrial swelling, leading to extensive cytoplasmic vacuolation. It can be induced by natural compounds, metallic complexes, nanoparticles, or chemotherapeutic agents, primarily through excessive ROS production and disruption of protein, thiol, and calcium/ion homeostasis. Autophagy and paraptosis have been found to be connected through crosstalk. While MAPK activation drives paraptosis, ER stress and the unfolded protein response (UPR) can initiate both paraptosis and autophagy. UPR-mediated PERK activation promotes survival autophagy in ER-stressed melanoma, whereas PERK elimination triggers paraptosis via sec61β with unresolved ER stress. Similarly, CHOP and DDIT4 can enhance ER stress and proteotoxicity, thereby favouring paraptosis. This review is unique in exploring the dynamic interplay between autophagy and paraptosis in cancer cells, highlighting promising therapeutic targets for chemotherapy-resistant cancers.

Cartilage is traditionally viewed as a metabolically quiescent tissue that relies primarily on exogenous lipid uptake to meet its energetic and structural demands. However, increasing evidence suggests that chondrocytes exhibit metabolically active behaviors, particularly under aging and pathological conditions. Here, we developed and applied an in vivo deuterium oxide (D ₂ O)–based stable isotope labeling approach to directly quantify de novo fatty‐acid synthesis in cartilage. Using gas chromatography–mass spectrometry (GC–MS), we tracked deuterium incorporation into palmitate in serum and articular cartilage from wild‐type (WT) and cartilage‐specific acetyl‐CoA carboxylase 1 (ACC1) knockout mice. Progressive incorporation of deuterium into palmitate confirmed active fatty‐acid synthesis in cartilage, with labeling kinetics distinct from those observed in serum, consistent with slower lipid turnover in the matrix‐dense cartilage environment. Although fractional new synthesis of palmitate was comparable between genotypes during the labeling window, ACC1‐deficient cartilage exhibited reduced palmitate abundance and decreased higher‐order isotopomer enrichment at early labeling time points, indicating attenuated lipogenic flux. These findings provide direct in vivo evidence that chondrocytes possess intrinsic lipogenic capacity and that ACC1 contributes to the maintenance of the cartilage lipid pool. Together, this study establishes D ₂ O‐based isotope tracing as a robust and quantitative framework for assessing cartilage lipid metabolism in vivo and reveals de novo lipogenesis as an active metabolic process in cartilage. Clinical Significance: This approach offers a valuable platform for investigating lipid dysregulation in osteoarthritis and other joint diseases.