Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease that typically features a dramatic desmoplastic reaction, especially fibroblasts. The roles of cancer-associated fibroblasts (CAFs) in PDAC have received more attention in recent years. As increasing evidence suggests the heterogeneity of CAFs in PDAC, different CAF subtypes have been shown to support tumor growth, while others suppress cancer proliferation. Myofibrotic CAFs (myCAFs) show alpha-smooth muscle actin (α-SMA)high interleukin-6 (IL-6)low myofibroblastic features, are activated by direct contact with tumor cells, and are located in the periglandular region. Inflammatory CAFs (iCAFs) show α-SMAlow IL-6high inflammatory features, are activated by paracrine factors secreted from tumor cells, and are located away from cancer cells. Antigen-presenting CAFs (apCAFs) show major histocompatibility complex II (MHC II) family genes that are highly expressed. CAFs have also been gradually explored as diagnostic and prognostic markers in pancreatic cancer. Targeted therapy of CAFs in PDAC has gradually attracted attention. With the deepening of related studies, some meaningful positive and negative results have surfaced, and CAFs may be the key to unlocking the door to pancreatic cancer treatment. Our review summarizes recent advances in the heterogeneity, function, and markers of CAFs in pancreatic cancer, as well as research and treatment targeting CAFs in pancreatic cancer.

Acute pancreatitis (AP) is a leading cause of death and is commonly accompanied by systemic manifestations that are generally associated with a poor prognosis. Many cytokines contribute to pancreatic tissue damage and cause systemic injury. Interleukin-17 (IL-17) is a cytokine that may play a vital role in AP. Specifically, IL-17 has important effects on the immune response and causes interactions between different inflammatory mediators in the AP-related microenvironment. In this literature review, we will discuss the existing academic understanding of IL-17 and the impacts of IL-17 in different cells (especially in acinar cells and immune system cells) in AP pathogenesis. The clinical significance and potential mechanisms of IL-17 on AP deterioration are emphasized. The evidence suggests that inhibiting the IL-17 cytokine family could alleviate the pathogenic process of AP, and we highlight therapeutic strategies that directly or indirectly target IL-17 cytokines in acute pancreatitis.

Background and Purpose: Gut microbiota dysbiosis induced by acute pancreatitis (AP) exacerbates pancreatic injury and systemic inflammatory responses. The alleviation of gut microbiota dysbiosis through faecal microbiota transplantation (FMT) is considered a potential strategy to reduce tissue damage and inflammation in many clinical disorders. Here, we aim to investigate the effect of gut microbiota and microbiota-derived metabolites on AP and further clarify the mechanisms associated with pancreatic damage and inflammation. Experimental Approach: AP rat and mouse models were established by administration of caerulein or sodium taurocholate in vivo. Pancreatic acinar cells were exposed to caerulein and lipopolysaccharide in vitro to simulate AP. Key Results: Normobiotic FMT alleviated AP-induced gut microbiota dysbiosis and ameliorated the severity of AP, including mitochondrial dysfunction, oxidative damage and inflammation. Normobiotic FMT induced higher levels of NAD + (nicotinamide adenine dinucleotide)-associated metabolites, particularly nicotinamide mononucleotide (NMN). NMN administration mitigated AP-mediated mitochondrial dysfunction, oxidative damage and inflammation by increasing pancreatic NAD + levels. Similarly, overexpression of the NAD + -dependent mitochondrial deacetylase sirtuin 3 (SIRT3) alleviated the severity of AP. Furthermore, SIRT3 deacetylated peroxiredoxin 5 (PRDX5) and enhanced PRDX5 protein expression, thereby promoting its antioxidant and anti-inflammatory activities in AP. Importantly, normobiotic FMTmediated NMN metabolism induced SIRT3-PRDX5 pathway activation during AP. Conclusion and Implications: Gut microbiota-derived NMN alleviates the severity of AP by activating the SIRT3-PRDX5 pathway. Normobiotic FMT could be served as a potential strategy for AP treatment.

Pancreatic ductal adenocarcinoma (PDAC) presents with high mortality and short overall survival. Cancer‐associated fibroblasts (CAFs) act as refuge for cancer cells in PDAC. Mechanisms of intracelluar communication between CAFs and cancer cells need to be explored. Long noncoding RNAs (lncRNAs) are involved in the modulation of oncogenesis and tumor progression of PDAC; however, specific lncRNAs and their mechanism of action have not been clarified clearly in tumoral microenvironment. This work aims to identify novel lncRNAs involved in cellular interaction between cancer cells and CAFs in PDAC. To this end, differentially expressed lncRNAs between long‐term and short‐term survival PDAC patients are screened. Lnc‐FSD2‐31:1 is found to be significantly increased in long‐term survival patients. This work then discovers that tumor‐derived lnc‐FSD2‐31:1 restrains CAFs activation via miR‐4736 transported by extracellular vesicles (EVs) in vitro and in vivo. Mechanistically, EVs‐derived miR‐4736 suppresses autophagy and contributes to CAFs activation by targeting ATG7. Furthermore, blocking miR‐4736 suppresses tumor growth in genetically engineered KPC (LSL‐KrasG12D/+, LSL‐Trp53R172H/+, and Pdx‐1‐Cre) mouse model of PDAC. This study demonstrates that intratumoral lnc‐FSD2‐31:1 modulates autophagy in CAFs resulting in their activation through EVs‐derived miR‐4736. Targeting miR‐4736 may be a potential biomarker and therapeutic target for PDAC.