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Category: 3. Business

  • Exclusive | Bill Ackman Eyes Simultaneous Public Offerings of Firm and New Fund – The Wall Street Journal

    1. Exclusive | Bill Ackman Eyes Simultaneous Public Offerings of Firm and New Fund  The Wall Street Journal
    2. Bill Ackman plots IPO of hedge fund Pershing Square in early 2026  Financial Times
    3. Bill Ackman Wants To Take His Hedge-Fund Management Company, Pershing Square, Public At The Same Time As A New Closed-End Fund Next Year – WSJ  TradingView
    4. Bill Ackman eyes IPO of hedge fund Pershing in early 2026, FT reports  104.1 WIKY
    5. Bill Ackman’s Pershing Square reportedly planning IPO in early 2026  MSN

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  • World's biggest nuclear plant edges closer to restart – Japan Today

    1. World’s biggest nuclear plant edges closer to restart  Japan Today
    2. Japan edges closer to restarting world’s biggest nuclear power plant Kashiwazaki-Kariwa  BBC
    3. TEPCO set for March nuclear restart, first since Fukushima disaster  Nikkei Asia
    4. Tokyo Electric (TKECF) Secures Key Approval for Nuclear Plant Re  GuruFocus
    5. Niigata governor consents to restart of Kashiwazaki-Kariwa reactors  World Nuclear News

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  • A Fresh Look at SiTime (SITM) Valuation Following Recent Share Price Uptick

    A Fresh Look at SiTime (SITM) Valuation Following Recent Share Price Uptick

    SiTime (SITM) shares have moved slightly higher over the last day, adding almost 6% despite no major news event driving the uptick. The recent trading performance comes after a steady month and strong returns this year.

    See our latest analysis for SiTime.

    SiTime’s 1-day share price return of nearly 6% adds to an already impressive year, with its total shareholder return at 26.9% over the past twelve months and a staggering 203.5% for investors holding since 2019. Although the pace has fluctuated in recent weeks, momentum for the stock remains strong and is attracting attention as optimism around its growth story builds.

    If you’re searching for your next standout idea, now is a great opportunity to broaden your watchlist and discover fast growing stocks with high insider ownership

    With impressive returns and a strong growth trajectory, the vital question now is whether SiTime’s current valuation leaves room for upside, or if the market has already accounted for all its future potential.

    SiTime’s most widely followed narrative places its fair value well above the latest close, suggesting significant untapped upside. This perspective is built on rising expectations for product innovation and robust revenue acceleration.

    Expansion of SiTime’s content per device, particularly through customized clocks and clocking systems for AI, networking, and hyperscale platforms, enables increased dollar content per design win. This directly supports top-line growth and improves gross margins as these higher-ASP products become a greater share of sales.

    Read the complete narrative.

    Curious what’s fueling this bullish stance? The narrative hinges on aggressive assumptions around future sales expansion, margin inflection, and a valuation multiple you don’t usually see outside hyper-growth tech. One tweak to the forecasts and the whole story could shift. Don’t miss the pro-level modeling that underpins this price target.

    Result: Fair Value of $346 (UNDERVALUED)

    Have a read of the narrative in full and understand what’s behind the forecasts.

    However, risks remain, such as SiTime’s reliance on rapidly evolving AI data center demand as well as potential disruptions from innovation cycles or shifting customer dynamics.

    Find out about the key risks to this SiTime narrative.

    Looking at valuation from a price-to-sales perspective, SiTime trades at 24.8 times sales. That is far higher than both the US Semiconductor industry average of 4.2x and the peer average of 7.7x. The fair ratio is estimated at 12.5x, highlighting a substantial premium.

    What does this premium mean for risk and future upside? Could the market be overestimating SiTime’s growth story, or is innovation strong enough to justify this stretch valuation?

    See what the numbers say about this price — find out in our valuation breakdown.

    NasdaqGM:SITM PS Ratio as at Nov 2025

    If you see the story differently or want to dive deeper into the numbers, you can build your own take on SiTime in just a few minutes with Do it your way.

    A great starting point for your SiTime research is our analysis highlighting 2 key rewards and 2 important warning signs that could impact your investment decision.

    Don’t let the best opportunities pass you by. Use the Simply Wall Street Screener now to spot market movers and discover new stocks worth your attention.

    This article by Simply Wall St is general in nature. We provide commentary based on historical data and analyst forecasts only using an unbiased methodology and our articles are not intended to be financial advice. It does not constitute a recommendation to buy or sell any stock, and does not take account of your objectives, or your financial situation. We aim to bring you long-term focused analysis driven by fundamental data. Note that our analysis may not factor in the latest price-sensitive company announcements or qualitative material. Simply Wall St has no position in any stocks mentioned.

    Companies discussed in this article include SITM.

    Have feedback on this article? Concerned about the content? Get in touch with us directly. Alternatively, email editorial-team@simplywallst.com

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  • A dual-domain seasonal hybrid forecasting strategy for PV power considering dynamic uncertain fluctuations

  • Liu, Z. L. et al. Prediction of long-term photovoltaic power generation in the context of climate change. Renew. Energy. 235, 13 (2024).

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  • Fed Divisions Show Powell Isn’t the Biggest Hurdle to a Rate Cut – The Wall Street Journal

    1. Fed Divisions Show Powell Isn’t the Biggest Hurdle to a Rate Cut  The Wall Street Journal
    2. Probability of Interest Rate Cut by the Federal Reserve in December Rises to 71.3%  Binance
    3. Week Ahead: Markets on Edge as Fed Uncertainty Fuels Gold & Oil Volatility  VT Markets
    4. Economic Outlook  Federal Reserve Bank of Philadelphia
    5. Fed’s Paulson is ‘cautiously’ approaching December rate decision, she says  Reuters

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  • Trial Data Yield Risk-Based NRSTS Treatment Strategies

    Trial Data Yield Risk-Based NRSTS Treatment Strategies

    A new report affirms that surgical resection is generally sufficient for pediatric patients with low-risk non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) and suggests that patients with completely resected high-risk tumors do not necessarily benefit from adjuvant radiation.

    The findings, which were published in Pediatric Blood & Cancer, were based on findings from 2 trials that were designed to help develop a new risk-stratification system and compare different therapeutic regimens for patients with different risk profiles.1

    Corresponding author Monika Sparber-Sauer, MD, of the Stuttgart Cancer Center, in Germany, and colleagues, wrote that the current standard of care for pediatric NRSTS is based around surgical resection.

    “Primary tumor resection with wide margins in the NRSTS treatment mainstay, and is safe without further adjuvant treatment for low-risk disease,” they wrote.

    In unresectable tumors, neoadjuvant radiotherapy and/or chemotherapy can be used in hopes of facilitating later resection, as these patients have a low chance of a cure, they added. However, they said the role—or lack thereof—of adjuvant chemotherapy or radiotherapy in patients with primarily resected NRSTS remains an open question.

    The new study is based on data from two prospective trials, the CWS-96 and CWS-2002P trials, both of which were designed to limit chemotherapy and radiotherapy by using a risk-based treatment strategy.2,3

    Between the 2 trials, a total of 1,249 patients with localized NRSTS were enrolled (483 in CWS-96 and 445 in CWS-2002P). In the former, patients were risk-stratified based on Intergroup Rhabdomyosarcoma Study (IRS) group, histology, and grade. In the CWS-2002P trial, patients were stratified based on IRS group, lymph node status, tumor histology, and tumor size.

    In both trials, low-risk patients were treated with surgical resection alone. Standard-risk patients in both trials were given hyperfractionated accelerated radiotherapy (HART) by 44.8 Gy. In CWS-96, adjuvant chemotherapy with vincristine, actinomycin-D, ifosfamide, and 160–240 mg/m2 adriamycin (VAIA) was added for high-grade tumors, Sparber-Sauer and colleagues said.

    High-risk patients were given 6 cycles of VAIA in CWS-96 and an intensified adriamycin regimen (VAIA-III, 320 mg/m2 adriamycin) in CWS-2002P, along with delayed resection and/or 44.8 Gy radiotherapy. In some patients in CWS-2002P, maintenance treatment with cyclophosphamide and vinblastine was also given, the authors said.

    Overall, the investigators said patients in the CWS-2002P trial had a superior 5-year overall survival (OS; 81% versus 73%; P = 0.024), which they said was partly a result of the CWS-2002P trial’s inclusion of a greater number of entities like fibromyxoid sarcoma, which have a lower metastatic potential. The investigators added that improvements in surveillance, imaging, and surgical techniques over time also likely affected the outcomes.

    “We found that the IRS group alone was a strong predictor of EFS (event-free survival) and OS; despite incorporating multiple independent risk factors in CWS-2002P—including IRS, histology, lymph node size, and initial tumor size—no refinement to the risk-stratification system was achieved,” they said.

    Though CWS-2002P had improved OS in general, Sparber-Sauer and colleagues said the higher dose of anthracycline used in that trial did not appear to improve survival.

    Furthermore, they said low-risk patients who underwent surgery alone had a 5-year EFS and OS of 82% and 93% across both trials, suggesting that surgery alone is sufficient in most cases.

    “One remaining question is the role of chemotherapy in standard-risk disease,” they said. That’s because while radiotherapy alone was recommended for standard-risk patients in the CWS-2002P trial, in real-world usage clinicians often gave both chemotherapy and radiotherapy, as was the recommendation in the CWS-96 trial. Thus, the authors said, it is not possible to draw clear conclusions.

    Sparber-Sauer and colleagues concluded that in high-risk patients, clinicians should seek out entity-specific clinical trial data whenever possible.

    “Where no clinical trial is available, vincristine and actinomycin-D can be omitted, and the ifosfamide/doxorubicin regimen should be used, preferably with a reduced anthracycline dose in postoperative chemotherapy cycles,” they wrote.

    They added that their finding that high-risk patients undergoing R0 resection have a comparable prognosis to patients with high-risk disease who receive radiation following incomplete resection warrants further investigation.

    References

    1. Heinz AT, Schönstein A, Koscielniak E, et al. Children and Adolescents With Localised Non-Rhabdomyosarcoma Soft Tissue Sarcoma: Results of the CWS-96 and CWS-2002P Prospective Trials With Reclassification of the Trial Data Incorporating the Recent Soft Tissue Sarcoma Registry. Pediatr Blood Cancer. Published online November 11, 2025. doi:10.1002/pbc.32159
    2. Sparber-Sauer M, Ferrari A, Kosztyla D, et al. Long-term results from the multicentric European randomized phase 3 trial CWS/RMS-96 for localized high-risk soft tissue sarcoma in children, adolescents, and young adults. Pediatr Blood Cancer. 2022;69(9):e29691. doi:10.1002/pbc.29691
    3. Koscielniak E, Blank B, Vokuhl C, et al. Long-term clinical outcome and prognostic factors of children and adolescents with localized rhabdomyosarcoma treated on the CWS-2002P protocol. Cancers (Basel). 2022;14(4):899. doi:10.3390/cancers14040899

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  • Merck Recommends Rejection of Tutanota’s “Mini-Tender” Offer

    Merck Recommends Rejection of Tutanota’s “Mini-Tender” Offer

    RAHWAY, N.J., November 22, 2025–(BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside the United States and Canada, has been notified that Tutanota LLC (Tutanota) has commenced an unsolicited “mini-tender” offer, dated November 10, 2025, to purchase up to 1,000,000 shares of Merck common stock at $65.00 per share. The offer price is approximately 24.66% below the closing price of Merck common stock on November 7, 2025 ($86.28), the last trading day before the date of the offer, and approximately 31.56% below the closing price of Merck common stock on November 20, 2025 ($94.97), the day prior to this release.

    Merck does not endorse Tutanota’s offer and recommends that Merck shareholders reject the offer and not tender their shares in response to Tutanota’s unsolicited mini-tender offer. This mini-tender offer is at a price below the closing price for Merck’s shares (as of the day prior to this release) and is subject to numerous conditions, including Tutanota’s ability to obtain financing. Merck is not associated in any way with Tutanota, its mini-tender offer or the offer documentation.

    Tutanota has made similar unsolicited mini-tender offers for shares of other publicly traded companies. Mini-tender offers seek to acquire less than 5% of a company’s outstanding shares. This lets the offering company avoid many of the disclosure and procedural requirements the U.S. Securities and Exchange Commission (SEC) requires for tender offers. As a result, mini-tender offers do not provide investors the same level of protections as provided by larger tender offers under U.S. federal securities laws.

    On its website, the SEC advises that the people behind mini-tender offers “frequently use mini-tender offers to catch shareholders off guard” and that investors “may end up selling at below-market prices.” The SEC’s website also contains important tips for investors regarding mini-tender offers.

    Like Tutanota’s other offers, this one puts individual investors at risk because they may not realize they are selling their shares at a discount. Merck urges shareholders to obtain current stock quotes for their shares of Merck common stock, to review the terms and conditions of the offer, to consult with their brokers or financial advisers, and to exercise caution with respect to Tutanota’s mini-tender offer.

    Merck shareholders who have already tendered are advised they may withdraw their shares by following the procedures for withdrawal described in the Tutanota offer documents prior to the expiration of the offer, which is currently scheduled for 5:00 p.m. EST on December 15, 2025.


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  • Merck Recommends Rejection of Tutanota’s “Mini-Tender” Offer

    RAHWAY, N.J.–(BUSINESS WIRE)–
    Merck (NYSE: MRK), known as MSD outside the United States and Canada, has been notified that Tutanota LLC (Tutanota) has commenced an unsolicited “mini-tender” offer, dated November 10, 2025, to purchase up to 1,000,000 shares of Merck common stock at $65.00 per share. The offer price is approximately 24.66% below the closing price of Merck common stock on November 7, 2025 ($86.28), the last trading day before the date of the offer, and approximately 31.56% below the closing price of Merck common stock on November 20, 2025 ($94.97), the day prior to this release.

    Merck does not endorse Tutanota’s offer and recommends that Merck shareholders reject the offer and not tender their shares in response to Tutanota’s unsolicited mini-tender offer. This mini-tender offer is at a price below the closing price for Merck’s shares (as of the day prior to this release) and is subject to numerous conditions, including Tutanota’s ability to obtain financing. Merck is not associated in any way with Tutanota, its mini-tender offer or the offer documentation.

    Tutanota has made similar unsolicited mini-tender offers for shares of other publicly traded companies. Mini-tender offers seek to acquire less than 5% of a company’s outstanding shares. This lets the offering company avoid many of the disclosure and procedural requirements the U.S. Securities and Exchange Commission (SEC) requires for tender offers. As a result, mini-tender offers do not provide investors the same level of protections as provided by larger tender offers under U.S. federal securities laws.

    On its website, the SEC advises that the people behind mini-tender offers “frequently use mini-tender offers to catch shareholders off guard” and that investors “may end up selling at below-market prices.” The SEC’s website also contains important tips for investors regarding mini-tender offers.

    Like Tutanota’s other offers, this one puts individual investors at risk because they may not realize they are selling their shares at a discount. Merck urges shareholders to obtain current stock quotes for their shares of Merck common stock, to review the terms and conditions of the offer, to consult with their brokers or financial advisers, and to exercise caution with respect to Tutanota’s mini-tender offer.

    Merck shareholders who have already tendered are advised they may withdraw their shares by following the procedures for withdrawal described in the Tutanota offer documents prior to the expiration of the offer, which is currently scheduled for 5:00 p.m. EST on December 15, 2025.

    Merck encourages brokers, dealers, and other investors to review the SEC’s letter regarding broker-dealer mini-tender offer dissemination and disclosure.

    Merck requests that a copy of this news release be included with all distribution of materials related to Tutanota’s offer for shares of Merck common stock.

    About Merck

    At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn.

    Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA

    This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

    Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

    The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2024 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).


    Source: Merck & Co., Inc., Rahway, NJ, USA


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  • Merck Recommends Rejection of Tutanota’s “Mini-Tender” Offer

    RAHWAY, N.J.–(BUSINESS WIRE)–
    Merck (NYSE: MRK), known as MSD outside the United States and Canada, has been notified that Tutanota LLC (Tutanota) has commenced an unsolicited “mini-tender” offer, dated November 10, 2025, to purchase up to 1,000,000 shares of Merck common stock at $65.00 per share. The offer price is approximately 24.66% below the closing price of Merck common stock on November 7, 2025 ($86.28), the last trading day before the date of the offer, and approximately 31.56% below the closing price of Merck common stock on November 20, 2025 ($94.97), the day prior to this release.

    Merck does not endorse Tutanota’s offer and recommends that Merck shareholders reject the offer and not tender their shares in response to Tutanota’s unsolicited mini-tender offer. This mini-tender offer is at a price below the closing price for Merck’s shares (as of the day prior to this release) and is subject to numerous conditions, including Tutanota’s ability to obtain financing. Merck is not associated in any way with Tutanota, its mini-tender offer or the offer documentation.

    Tutanota has made similar unsolicited mini-tender offers for shares of other publicly traded companies. Mini-tender offers seek to acquire less than 5% of a company’s outstanding shares. This lets the offering company avoid many of the disclosure and procedural requirements the U.S. Securities and Exchange Commission (SEC) requires for tender offers. As a result, mini-tender offers do not provide investors the same level of protections as provided by larger tender offers under U.S. federal securities laws.

    On its website, the SEC advises that the people behind mini-tender offers “frequently use mini-tender offers to catch shareholders off guard” and that investors “may end up selling at below-market prices.” The SEC’s website also contains important tips for investors regarding mini-tender offers.

    Like Tutanota’s other offers, this one puts individual investors at risk because they may not realize they are selling their shares at a discount. Merck urges shareholders to obtain current stock quotes for their shares of Merck common stock, to review the terms and conditions of the offer, to consult with their brokers or financial advisers, and to exercise caution with respect to Tutanota’s mini-tender offer.

    Merck shareholders who have already tendered are advised they may withdraw their shares by following the procedures for withdrawal described in the Tutanota offer documents prior to the expiration of the offer, which is currently scheduled for 5:00 p.m. EST on December 15, 2025.

    Merck encourages brokers, dealers, and other investors to review the SEC’s letter regarding broker-dealer mini-tender offer dissemination and disclosure.

    Merck requests that a copy of this news release be included with all distribution of materials related to Tutanota’s offer for shares of Merck common stock.

    About Merck

    At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable and healthy future for all people and communities. For more information, visit www.merck.com and connect with us on X (formerly Twitter), Facebook, Instagram, YouTube and LinkedIn.

    Forward-Looking Statement of Merck & Co., Inc., Rahway, N.J., USA

    This news release of Merck & Co., Inc., Rahway, N.J., USA (the “company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

    Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

    The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2024 and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).


    Source: Merck & Co., Inc., Rahway, NJ, USA


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  • New Proteomic Analysis Maps Cytokine Signatures Driving IPF

    New Proteomic Analysis Maps Cytokine Signatures Driving IPF

    A new proteomic analysis is shedding a fresh light on the cytokine networks fueling idiopathic pulmonary fibrosis (IPF), identifying a set of differentially expressed signaling proteins and potential drug targets that may help reshape future therapeutic strategies for one of the most challenging interstitial lung diseases (ILDs) to treat.

    The integrative proteomic study provides one of the most comprehensive views to date of cytokine abnormalities in IPF. By defining core signaling hubs, immune-cell associations, and potential therapeutic targets, the research offers new molecular signposts for drug development—an urgent need for a disease that remains fatal for most patients despite current treatments.

    “While pirfenidone and nintedanib (the only antifibrotic drugs currently approved for treating IPF) can slow lung function decline, their efficacy in halting pulmonary fibrosis progression and enhancing patients’ quality of life remains limited,” wrote the researchers. “Additionally, there are concerns regarding drug resistance and adverse effects. Therefore, safe and effective pharmacological agents are urgently needed.”

    The new findings, generated from cytokine profiling of lung tissue and supported by bioinformatics, single-cell sequencing, and drug–gene interaction mapping, offer a high-resolution look into the molecular dysregulation underlying fibrosis.

    IPF is defined by relentless scarring of lung tissue, eventual respiratory failure, and a median survival between 3 and 5 years.2 Although decades of research have highlighted roles for transforming growth factor-β (TGF-β) and other profibrotic mediators, no study until now has systematically examined hundreds of cytokines directly within human lung tissue. In the current work, detailed in Canadian Respiratory Journal, researchers collected explanted lungs from 5 individuals undergoing transplantation for IPF and compared them with donor control lungs. Using high-throughput protein microarrays capable of detecting 440 cytokines, the team constructed one of the most detailed IPF cytokine maps to date.

    The analysis identified 32 differentially expressed proteins (DEPs) between IPF and control lungs, with 11 upregulated and 21 downregulated. Many of these proteins have been previously associated with IPF development, including chemokines, matrix-remodeling enzymes, and receptors involved in immune signaling. The expression patterns were sufficiently distinct to separate IPF and control samples through principal component analysis, emphasizing that cytokine dysregulation is a defining molecular feature of the disease.

    Functional enrichment analysis revealed that these DEPs were highly concentrated in pathways associated with cell chemotaxis, growth factor binding, PI3K–Akt signaling, MAPK signaling, and cytokine–receptor interactions—all known contributors to fibroblast activation, epithelial injury, and extracellular matrix accumulation. Additional gene-set enrichment analysis performed across all 440 measured cytokines highlighted enrichment of biological processes tied to peptide hormone signaling, nitrogen compound response, and insulin-response pathways, suggesting oversights in current models of IPF pathophysiology.

    To understand how these DEPs organize into functional networks, the researchers generated a protein–protein interaction map using STRING and identified 5 hub proteins with high centrality scores: FGF2, HGF, HBEGF, ERBB3, and ANGPT2. These molecules act as central communication nodes in cytokine signaling and growth-factor pathways, and their dysregulation may represent core drivers of IPF progression. One hub protein, HGF, showed the strongest functional similarity to other hub proteins, implying it may be especially critical in the broader cytokine network.

    The study also used transcription-factor prediction algorithms to map which upstream regulators may drive the expression of these hub proteins. Thirty-one transcription factors—including SP1, STAT3, HIF1A, and LMO2—emerged as potential regulatory controllers, underscoring the deep integration of cytokine signaling with inflammation, hypoxia, and wound-repair pathways.

    Since IPF is strongly linked to immune dysregulation, the team analyzed immune-cell infiltration using the CIBERSORT algorithm. Among 22 immune-cell types examined, resting natural killer (NK) cells were significantly more abundant in IPF lung tissue and were inversely correlated with HBEGF expression. This relationship suggests an underexplored interface between NK-cell activity and cytokine-driven injury repair.

    Recognizing the urgent need for new treatment strategies, investigators used the DGIdb database to explore whether the five hub proteins are targetable by existing drugs. The analysis surfaced 67 potential agents, 13 of which have prior evidence of antifibrotic or immunomodulatory effects. These include widely studied compounds such as sirolimus, imatinib, resveratrol, and atorvastatin, as well as chemotherapy agents used in patients with lung cancer and comorbid fibrosis. While these findings do not establish clinical efficacy, they highlight promising entry points for drug repurposing.

    Hub-protein expression was further validated in 3 independent GEO datasets and through immunohistochemistry on IPF lung tissue. Finally, single-cell RNA sequencing revealed the specific cellular sources of these cytokines—fibroblasts, myofibroblasts, macrophages, epithelial cells, and specialized vascular endothelial populations—confirming that cytokine dysregulation in IPF arises from multiple interacting cell types, not a single dominant driver.

    References

    1. Shen C, Wang W, Li G, et al. Cytokine expression profiling in idiopathic pulmonary fibrosis: insights from integrative proteomic analysis. Can Respir J. Published online November 7, 2025. doi:10.1155/carj/2272156
    2. Raghu G, Remy-Jardin M, Richeldi L, Thomson CC, Inoue Y, Johkoh T, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med 2022;205:e18–e47.

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