bims-stacyt 2025-12-21 papers

Biochim Biophys Acta Mol Basis Dis. 2025 Dec 17. pii: S0925-4439(25)00494-6. [Epub ahead of print] 168144

The effects of tissue inflammation on cancer cachexia.

Cancer cachexia is characterized by a significant loss in body weight due to the wasting of skeletal muscle and adipose tissue. Systemic inflammation has long been associated with cachexia, with various tumor secreted factors shown to correlate with as well as cause tissue wasting. In addition to systemic inflammation, it has become increasingly appreciated that inflammation occurs in specific tissues in cancer cachexia, with tissues such as muscle, adipose, liver and brain being affected. While several studies have shown that this local tissue inflammation contributes to cachexia, there is evidence that some aspects of the inflammatory response may play a protective role to mitigate tissue wasting. Here, we will review the findings on local tissue inflammation in cachexia, comparing the impacts of such inflammation on tissue wasting and cachexia progression overall. Furthermore, we discuss the methods used to mitigate inflammation in various tissues and highlight the outcomes on the cachectic phenotype. Collectively, understanding how inflammation contributes to cachexia in each tissue will ultimately influence how therapies can be designed to treat cachexia while minimizing possible adverse side effects.

Keywords: Cancer Cachexia; Inflammation; Macrophage

DOI: https://doi.org/10.1016/j.bbadis.2025.168144

FASEB J. 2025 Dec 31. 39(24): e71372

Interaction Between Activating Transcription Factor 4 and Interleukin 6 Dictates Osteoclast Differentiation and Activity.

Shasha Tu, Sijun Liu, Mengmeng Duan, Jiazhou Li, Li Zhang, Jie Ren, Ting Zhao, Jing Xie, Xiaoheng Liu.

Osteoclast functioning determines homeostasis of bone texture, healing speed after bone injury, and integrity after bone remodeling. Osteoclastogenesis is tightly controlled by transcriptional factors and cytokine-mediated signaling. The activating transcription factor 4 (Atf4) and interleukin 6 (IL6) have been considered to be involved in osteoclastogenesis, but their interaction on osteoclast differentiation is still largely unclear. Here we aimed to investigate their interaction on osteoclast differentiation and activity. Through lentiviral overexpression and siRNA transfection, we showed that Atf4 regulated osteoclastogenesis by upregulating the expression of osteoclast markers, including Nfatc1, c-Fos, Dcst1, Mmp2 and 9, and cathepsin K. Atf4-mediated osteoclastogenesis was largely dependent on activation of IL6 signaling through the direct binding of Atf4 to the IL6 promoter by ChIP assay. Atf4-IL6 axis activated the Jak1/Stat3 signaling to promote the formation of large, multinucleated osteoclasts. Taken together, these results indicate the important interaction between Atf4 and IL6 signaling on osteoclast differentiation beyond canonical MCSF and RANKL signaling and emphasize the multi-regulatory mechanism of Atf4-mediated osteoclastogenesis, which provides us with understanding of osteoporotic diseases and cues for therapeutic strategies.

Keywords: Atf4; IL6; Jak1/Stat3 pathway; knockdown; osteoclastogenesis; overexpression

DOI: https://doi.org/10.1096/fj.202503503R

Nat Commun. 2025 Dec 17.

Loss of ALK4 promotes cancer progression through regulating TGF-β receptor N-glycosylation.

Manqi Zhang, Jian Chen, Mary C Leupold, Jennifer Guo, Xiangfeng Shen, Carl A Shirley, Christen A Khella, Rushabh N Mehta, Edward T O'Brien, Michael L Gatza, Gerard C Blobe.

The transforming growth factor-β (TGF-β) pathway typically inhibits tumorigenesis but can promote metastasis during cancer progression. Activin receptor-like kinase 4 (ALK4), a type I TGF-β family receptor, is frequently downregulated or mutated in cancers, and reduced ALK4 expression correlates with poorer outcomes. However, its role and mechanism of action in cancer progression remains unclear. We demonstrate that ALK4 loss enhances anchorage-independent growth, migration, invasion, and epithelial-mesenchymal transition in vitro, as well as cancer progression in breast and pancreatic cancer models in vivo. Importantly, ALK4 loss promotes canonical TGF-β signaling by increasing TGF-β receptor N-linked glycosylation and stabilizing these receptors at the cell surface. Mechanistically, ALK4 loss upregulates β1,6 N-acetylglucosaminyltransferase V (MGAT5) and galectin-3, which binds MGAT5-modified glycoproteins to stabilize surface receptors. Consistent with prior observations that galectin-3 preferentially binds to MGAT5-modified glycoproteins to stabilize cell surface receptors like TGF-β receptors, we demonstrate that ALK4 loss enhances MGAT5-mediated glycosylation of TGF-β receptors, promoting their stabilization and signal transduction. Depleting MGAT5 or inhibiting N-glycosylation effectively suppresses ALK4-loss-induced TGF-β signaling and cancer progression.

DOI: https://doi.org/10.1038/s41467-025-67563-1

Mol Metab. 2025 Dec 17. pii: S2212-8778(25)00216-9. [Epub ahead of print] 102309

Effect of free fatty acids on TGF-β1 mediated fibrogenesis in hepatic stellate cells.

William De Nardo, Jacqueline Bayliss, Sheik Nadeem Elahee Doomun, Olivia Lee, Paula M Miotto, Natasha D Suriani, Shuai Nie, Michael Leeming, Diego A Miranda, David P De Souza, Matthew J Watt.

/ OBJECTIVE: Metabolic associated steatotic liver disease (MASLD) is the most prevalent liver disorder and a major risk factor for hepatic fibrosis. Activated hepatic stellate cells (HSCs) are the primary source of collagen production in the liver, contributing to fibrosis. However, the mechanisms by which HSCs reprogram their metabolism to support sustained collagen production, particularly in a lipid-rich environment such as MASLD, remain inadequately understood. In this study, we investigated the effect of extracellular fatty acids on HSC substrate metabolism, HSC activation, and collagen synthesis.
METHODS: Immortalized human HSCs (LX-2 cells) were cultured with or without transforming growth factor-beta 1 (TGF-β1) and varying concentrations of palmitate or oleate. Cellular lipid composition was assessed by mass spectrometry lipidomics. Fatty acid metabolism was assessed using radiometric techniques and isotopic labelling experiments using 13C-glucose or 13C-palmitate. HSC activation was assessed by measuring ACTA2, TGFB1, and COL1A1 mRNA levels and collagen secretion by ELISA.
RESULTS: TGF-β1 reduced the abundance of many lipid types in LX-2 cells. Exogenous palmitate did not increase HSC activation, as determined by ACTA2, TGFB1, COL1A1 mRNA levels. Palmitate potentiated TGF-β1 induced collagen secretion but not in the presence of oleate. Palmitate reduced glucose incorporation into glycine in activated HSCs and induced a reciprocal increase in palmitate incorporation into glycine, most likely via carbons derived from TCA cycle intermediates. Pharmacological inhibition of fatty acid uptake reduced TGF-β1-mediated collagen secretion.
CONCLUSIONS: These results suggest that in activated HSCs, palmitate oxidation is reduced and that TCA cycle intermediates derived from palmitate are used as carbon sources for amino acid production that supports collagen synthesis and secretion.

Keywords: Hepatic stellate cell; MASLD; collagen; lipid metabolism; liver fibrosis; metabolic reprogramming; palmitate

DOI: https://doi.org/10.1016/j.molmet.2025.102309

Nat Commun. 2025 Dec 13.

Inhibiting translation elongation by reducing eIF5A activity induces feedback inhibition of initiation, limiting tumour cell proliferation.

Cancer development is associated with dysregulation of the translatome, and targeting canonical eukaryotic initiation and elongation factors can offer treatment avenues for various neoplasms. Emerging evidence indicates that dysregulated mRNA elongation, involving alterations in eEF2 activity and eIF5A expression, also contributes to tumour cell growth. In this study, we investigate whether targeting eIF5A with the inhibitor GC7 is a viable strategy to curtail aberrant cell growth. Our findings demonstrate that inhibiting elongation by reducing eIF5A activity induces feedback inhibition of initiation through eIF2α phosphorylation, decreasing ternary complex formation and shutting down bulk protein synthesis. Employing dynamic SILAC, we identify proteins impacted by reduced eIF5A activity, and show their decreased translation results from feedback inhibition to initiation or other processes downstream of eIF5A. Decreased eIF5A activity impairs mitochondrial function, which activates signalling through HRI to eIF2α phosphorylation, reducing cancer cell proliferation. These effects are reversed by treatment with the integrated stress response inhibitor, implying that the impact of GC7 on cancer cell proliferation is mediated via translation initiation rather than elongation inhibition. These data suggest that eIF5A inhibition could be used to target cancer cells that depend on mitochondrial function for their proliferation and survival.

DOI: https://doi.org/10.1038/s41467-025-66531-z

Clin Transl Med. 2025 Dec;15(12): e70556

Hypoxia-induced secretory autophagy in cancer-associated fibroblasts promotes ECM remodelling through serglycin secretion in oral squamous cell carcinoma.

Yan Zhang, Cheng Tao, Xiteng Yin, Zhi Wang, Yuyang Zhang, Jiale Yu, Yufeng Wang, Wei Han.

BACKGROUND: The worst pattern of invasion (WPOI) is a critical histological prognostic indicator in oral squamous cell carcinoma (OSCC), yet the underlying mechanisms driving high WPOI remain poorly understood. While cancer-associated fibroblasts (CAFs) and their secreted factor serglycin (SRGN) are implicated in tumour progression, the regulation of SRGN secretion within the hypoxic tumour microenvironment is unknown.
METHODS: We performed single-cell RNA sequencing (scRNA-seq) on 6 OSCC samples (3 each of WPOI 1-3 and 4-5) to identify subgroups of CAFs and their characteristic gene expression profiles. Using Western blot, qRT-PCR, and immunofluorescence, we investigated hypoxia-induced SRGN secretion pathways. Complementary CRISPR-Cas9 knockout, Co-IP assays, and xenograft models elucidated SRGN's role in ECM remodelling.
RESULTS: ScRNA-seq revealed significant enrichment of CAFs, particularly an SRGN-expressing myCAF subpopulation, in high-WPOI (4-5) OSCC tissues. Under hypoxia, CAFs switched SRGN secretion from the conventional ER-Golgi pathway to an unconventional secretory autophagy pathway, dependent on autophagosome formation but independent of lysosomal degradation. Secreted SRGN directly interacted with matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) in the extracellular matrix (ECM), enhancing ECM remodelling and OSCC invasion and migration. In vivo, either genetic ablation of SRGN in CAFs or pharmacological inhibition of autophagy significantly suppressed tumour growth, inhibited collagen I degradation, and restored E-cadherin expression.
CONCLUSION: Our study identifies a novel mechanism whereby hypoxia induces CAFs to secrete SRGN via secretory autophagy. This SRGN-MMP2/9 axis drives ECM remodelling and promotes OSCC invasion, which histologically manifests as high WPOI. Targeting secretory autophagy or SRGN represents a promising therapeutic strategy for aggressive OSCC.
KEY POINTS: Under normoxia, SRGN enters the conventional secretory pathway via the endoplasmic reticulum (ER) and Golgi apparatus for extracellular release. Under hypoxia, elevated autophagy levels in CAFs facilitate the release of SRGN into the ECM through secretory autophagy-mediated plasma membrane fusion. Within the ECM, SRGN interacts with MMP2 and MMP9, enhancing ECM remodelling and OSCC invasion.

Keywords: ECM remodelling; cancer‐associated fibroblasts; secretory autophagy; serglycin

DOI: https://doi.org/10.1002/ctm2.70556