Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction–associated steatohepatitis

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Recent clinical trials provided evidence that administration of autologous macrophage therapy for liver fibrosis is safe, although the nature of these trials precluded efficacy assessment.

“recent clinical trials have provided evidence that the administration of autologous macrophage therapy for liver fibrosis is safe, although the nature of these trials precluded efficacy assessment (52, 53).”

• cites [52] sourceSupported
• cites [53] sourceDisputed

  The Abstract reports that this phase 2 randomized controlled trial evaluated efficacy against standard care and tested a prespecified primary endpoint, which was not met. The Discussion supports the safety claim, but the assertion that the trial’s nature precluded efficacy assessment is contrary to the paper’s account; its design and sample size limited interpretation, not assessment. Page numbers were not supplied in our copy. (LLM, conf=0.89)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

May combine two claims.

HF-CDAA-fed mice develop hepatic steatosis at 2 weeks, early liver fibrosis at 4 weeks, and advanced liver fibrosis at 8 and 12 weeks.

“These mice develop hepatic steatosis at 2 weeks, early liver fibrosis at 4 weeks, and advanced liver fibrosis at 8 and 12 weeks of diet feeding (fig. S1A) (31, 32).”

• cites [31] sourcePartly supported

  The Results (Fig. 3; page unavailable) report fibrosis at 4 weeks (F1/2), 8 weeks (F2), and 12 weeks (F3), supporting the claimed fibrosis progression. The paper describes 4 weeks as the earliest time point tested and does not establish hepatic steatosis at 2 weeks. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites [32] sourcePartly supported

  The Results (page unavailable) report steatosis in most models and significant fibrosis in choline-deficient dietary models. The Discussion (page unavailable) says these diets can produce F2-or-higher fibrosis within 12 weeks. Neither passage establishes the claimed HF-CDAA progression—steatosis at 2 weeks, early fibrosis at 4 weeks, and advanced fibrosis at both 8 and 12 weeks. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

May combine two claims.

Previous work shows that TIM4 can act as an efferocytosis receptor and that TIM4 expression by liver macrophages is decreased in MASH.

“These findings are consistent with previous work showing that TIM4 can function as an efferocytosis receptor (21–23) and that TIM4 expression by liver macrophages is decreased in MASH (24–27).”

• cites [21] sourceNot checked — no full text of the source
• cites [22] sourceNot checked — no full text of the source
• cites [23] sourcePartly supported

  The Introduction and Discussion describe TIM-4 as an efferocytosis co-receptor, and the Results show that it facilitates efferocytosis by Kupffer cells. The paper reports decreased liver TIM-4 after ischemia and in Kupffer cells after LPS stimulation, but does not report decreased expression in MASH. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [24] sourceNot checked — no full text of the source
• cites [25] sourceNot checked — no full text of the source
• cites [26] sourceNot checked — no full text of the source
• cites [27] sourceSupported

Classified as probably not a substantial claim.

Previous reports outside MASH have suggested that IL-10 can lower HSC activation and liver fibrosis.

“previous reports not related to MASH have suggested that IL-10 can lower HSC activation and liver fibrosis (41–43).”

• cites [41] sourceNot checked — no full text of the source
• cites [42]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [43] sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Deletion of TREM2 in macrophages impairs efferocytosis ex vivo and worsens experimental MASH.

“Other groups have shown that deletion of triggering receptor expressed on myeloid cells 2 (TREM2) in macrophages impairs efferocytosis ex vivo and exacerbates experimental MASH (16–19)”

• cites [16] sourceSupported
  Experimental — accuracy not yet measured
• cites [17] sourcePartly supported

  Results §3.3 reports reduced clearance of apoptotic hepatocytes by isolated macrophages from Trem2-knockout mice. Results §3.4 reports greater steatosis and fibrosis in knockout mice fed a high-fat diet. The mice had a whole-body Trem2 knockout, however, so the paper does not establish that macrophage-specific deletion exacerbates experimental MASH. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [18] sourceNot checked — no full text of the source
• cites [19] sourcePartly supported

  The Results (pp. 3, 5) report that Trem2-deficient mice developed worse high-fat-diet-induced liver steatosis, hepatocyte ballooning and inflammatory changes, supporting the worsening-disease portion of the claim. The ex vivo macrophage experiments instead examine hepatocyte lipid metabolism and exosomes (Results, pp. 7–8); no passage found in searches for efferocytosis or apoptotic-cell engulfment reports impaired efferocytosis. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

Blocking either SIRPα or CD47 improved necroptotic hepatocyte uptake and dampened progression to liver fibrosis, but these manipulations did not lower apoptotic hepatocytes.

“Although blocking either SIRPα or CD47 improved necroptotic hepatocyte uptake and dampened the progression to liver fibrosis, these manipulations did not lower apoptotic hepatocytes (15).”

• cites [15] sourcePartly supported

  The Results and Discussion report that blocking either CD47 or SIRPα increased necroptotic hepatocyte uptake and reduced fibrosis in mouse NASH models. The Results also say anti-CD47 did not increase clearance of apoptotic hepatocytes, but that is not the same as showing that apoptotic hepatocyte numbers did not fall; the cited passages do not establish that outcome for either blockade. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

May combine two claims.

A key feature of MASH is hepatocyte apoptosis, which correlates with liver fibrosis.

“A key feature of MASH is hepatocyte apoptosis, which correlates with the clinically most important feature of the disease, liver fibrosis (6, 7).”

• cites [6] sourcePartly supported

  The “NASH and CLD” section says most data point to hepatocyte apoptosis as a key driver in NASH (now termed MASH). The “Fibroinflammation” section reports a correlation between apoptosis markers and fibrosis in patients, but does not establish that correlation specifically in MASH; the paper also discusses evidence that necroptosis may be important in NASH. Page numbers were unavailable in our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [7] sourceNot checked — no full text of the source

May combine two claims.

Clearance of necroptotic hepatocytes is impaired in MASH and contributes to MASH progression.

“In a previous study, we showed that the clearance of necroptotic hepatocytes is impaired in MASH, contributing to MASH progression (15)”

• cites [15] sourcePartly supported

  The Introduction says the authors hypothesized that failed clearance of necroptotic hepatocytes might promote NASH progression and that their findings support this hypothesis. The Discussion reports that promoting clearance in experimental NASH was associated with less fibrosis, but says it remains unclear how much of the improvement was due to clearance itself. The citing sentence presents that contribution as established more firmly than the paper does. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim. May combine two claims.

Previous work has shown that transgenic overexpression of IL-10 or IL-10 administration in mice reduced carbon tetrachloride-induced liver fibrosis, linked to decreased HSC activation ascribed to various mechanisms, including a decrease in CD4+ T cells and induction of HSC senescence.

“Previous work has shown that transgenic overexpression of IL-10 or IL-10 administration in mice reduced carbon tetrachloride–induced liver fibrosis, which was linked to decreased HSC activation ascribed to various mechanisms, including a decrease in CD4+ T cells and induction of HSC senescence (41–43).”

• cites [41] sourceNot checked — no full text of the source
• cites [42]Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [43] sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim. May combine two claims.

Efferocytosis prevents dead cell accumulation and reprograms macrophages for tissue resolution, and its impairment contributes to many chronic inflammatory diseases.

“Efferocytosis not only prevents dead cell accumulation but also reprograms macrophages to execute tissue resolution functions, and impaired efferocytosis contributes to many human chronic inflammatory diseases (12, 13).”

• cites [12] sourceSupported
• cites [13] sourceSupported

May combine two claims.

Clearance of necroptotic hepatocytes is also defective in steatohepatitis/MASH, but its mechanism involves increases in SIRPα on MASH liver macrophages and CD47 on necroptotic hepatocytes rather than a decrease in a specific macrophage receptor.

“We showed that the clearance of necroptotic hepatocytes is also defective in steatohepatitis/MASH, but the mechanism is due to increases in signal regulatory protein alpha (SIRPα) on MASH liver macrophages and CD47 on necroptotic hepatocytes rather than a decrease in a specific macrophage receptor (15).”

• cites [15] sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The MASH fibrosis-protective mechanisms of boosting apoptotic hepatocyte clearance and necroptotic hepatocyte clearance are distinct and complementary, suggesting a possible additive benefit of enhancing both processes.

“the MASH fibrosis–protective mechanisms of boosting apoptotic hepatocyte clearance (here) and necroptotic hepatocyte clearance (15) are distinct and complementary, suggesting a possible additive benefit of enhancing both processes by combination cell or RNA therapy.”

• cites [15] sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Efferocytosis in other settings can promote fibrosis as part of tissue resolution, for example, by secreting TGF-β1.

“efferocytosis in other settings can promote fibrosis as part of the tissue resolution process, for example, by secreting TGF-β1 (12, 13).”

• cites [12] sourcePartly supported

  The Conclusions (page unavailable) say a fibrotic response can follow efferocytosis. In “Myocardial infarction and heart failure” (page unavailable), the review says efferocytic myofibroblasts upregulate Tgfb and that their TGFβ production may promote excessive fibrosis. It does not establish secretion of TGF-β1 specifically or characterize that fibrosis as part of tissue resolution; it cautions that the fibrosis may be harmful. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [13] sourcePartly supported

  The Digestion phase says efferocytosis-associated signalling increases macrophage TGFβ expression, and the Cancer section describes possible TGFβ release by macrophages engulfing apoptotic cells. These passages support the secretion mechanism, but they do not say that efferocytosis promotes fibrosis during tissue resolution or identify the cytokine specifically as TGF-β1. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Defective macrophage efferocytosis drives the formation of clinically dangerous unstable atherosclerotic plaques.

“defective macrophage efferocytosis drives the formation of clinically dangerous (“unstable”) atherosclerotic plaques (57).”

• cites [57] sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Fibrotic MASH is an independent risk factor for atherosclerotic cardiovascular disease, which is the leading cause of death in people with MASH.

“fibrotic MASH is an independent risk factor for atherosclerotic cardiovascular disease, which is the leading cause of death in people with MASH (56).”

• cites [56] sourcePartly supported

  The Concluding remarks state that NASH is an independent risk factor for ASCVD and that ASCVD-related mortality exceeds liver-related mortality in people with NASH. The Introduction also calls cardiovascular disease the most common cause of death in this group. Neither passage establishes the independent-risk finding specifically for fibrotic NASH; the fibrosis discussion links advanced fibrosis to worse prognosis without making that ASCVD-specific claim (page numbers unavailable). (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Another efferocytosis receptor, TREM2, undergoes cleavage in MASH, and genetic deletion of Trem2 in mice is associated with MASH progression.

“Another efferocytosis receptor, TREM2, undergoes cleavage in MASH (16), and genetic deletion of Trem2 in mice is associated with MASH progression (16–19).”

• cites [16] sourceSupported
• cites [17] sourcePartly supported

  Results §3.3 identifies TREM2 as a phagocytic receptor, and Results §3.4 and the Discussion report worse liver damage and fibrosis after Trem2 deletion in mouse NAFLD/NASH models. The Discussion confirms increased soluble TREM2 in patients with NASH but says whether it arises from TREM2 cleavage remains unclear; it does not establish that TREM2 undergoes cleavage in MASH. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [18] sourceNot checked — no full text of the source
• cites [19] sourcePartly supported

  The Results (pp. 3, 5) report that Trem2 deletion worsened liver fat accumulation, hepatocyte ballooning and inflammatory-gene expression in high-fat-diet mice, supporting an association with worsening fatty liver disease. The paper calls this a NAFLD model, however, and our copy does not report TREM2 cleavage in MASH or characterize TREM2 as an efferocytosis receptor. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Uptake of apoptotic neutrophils by liver macrophages in CCl4-induced liver injury promotes TGF-β1-mediated HSC activation.

“whereas another study showed that the uptake of apoptotic neutrophils by liver macrophages in the setting of carbon tetrachloride (CCl4)–induced liver injury promotes TGF-β1–mediated HSC activation (46).”

• cites [46] sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Previous preclinical studies have shown that macrophage therapy can reduce carbon tetrachloride-induced liver fibrosis or promote repair of acute liver injury.

“Previous preclinical studies have shown that macrophage therapy can reduce carbon tetrachloride–induced liver fibrosis (47–50) or promote the repair of acute liver injury repair (44, 51).”

• cites [47] sourceNot checked — no full text of the source
• cites [48] sourceNot checked — no full text of the source
• cites [49] sourceSupported
• cites [50] sourceNot checked — no full text of the source
• cites [44] sourceNot checked — no full text of the source
• cites [51] sourceSupported

May combine two claims.

KC-TIM4-KD mice have lower liver Timd4 mRNA, while other efferocytosis receptor mRNAs remain similar to controls.

“liver Timd4 mRNA expression was decreased in KC-TIM4-KD mice, whereas the liver mRNAs of other efferocytosis receptors were similar between KD and control mice (fig. S2F).”

May combine two claims.

In the 16-week FPC model, KC-TIM4-KD increases CK19+ area and hCLS.

“The livers of the KD mice also had increases in CK19+ area (fig. S3N) and hCLS (fig. S3O).”

May combine two claims. The quote only partly states this claim.

Treatment with Timd4 macrophages raises liver TIM4, enhances efferocytosis, and lowers liver fibrosis in HF-CDAA-fed mice.

“cell therapy with TIM4+ macrophages enhanced apoptotic hepatocyte clearance and decreased HSC activation and liver fibrosis.”

May combine two claims.

Restoring macrophage TIM4 in the HF-CDAA model decreases HSC activation, bile ductular reaction, and hCLS.

“HSC activation (Fig. 4, F and G), bile ductular reaction (Fig. 4H), and hCLS (Fig. 4I).”

May combine two claims.

In FPC iTg mice, about 92% of TIM4 signal is in MAC2+ macrophages, similar to endogenous TIM4 in controls.

“91.6 ± 0.9% of the TIM4 signal was in MAC2+ macrophages versus MAC2− cells in the livers of the iTg mice, similar to endogenous TIM4 in control mice (95.6 ± 1.2% in MAC2+ versus MAC2− cells).”

May combine two claims.

In iTg mice, about 94% of TIM4 signal is in MAC2+ macrophages, similar to endogenous TIM4 in controls.

“93.9 ± 1.0% of the TIM4 signal was in MAC2+ (also known as galectin-3) macrophages versus MAC2− cells (non-macrophages) in the livers of the iTg mice, similar to endogenous TIM4 in control mice (95.5 ± 0.6% in MAC2+ versus MAC2− cells).”

May combine two claims.

Apoptotic hepatocytes build up in human MASH and in mouse models fed FPC or HF-CDAA diets.

“We show that apoptotic hepatocytes accumulate in human and experimental MASH, using mice fed the fructose-palmitate-cholesterol (FPC) diet or the high-fat, choline-deficient amino acid–defined (HF-CDAA) diet.”

May combine two claims.

KC-TIM4-KD changes in HF-CDAA-fed mice occur despite unchanged hepatosteatosis and only a modest fall in plasma ALT.

“These changes occurred despite no change in hepatosteatosis and only a modest decrease in plasma ALT activity (fig. S2, K and L).”

May combine two claims. The quote only partly states this claim.

KC-TIM4-KD in HF-CDAA-fed mice increases CK19+ area and hCLS.

“the KD mice had increased CK19+ area and hCLS (Fig. 3, G and H).”

May combine two claims.

In the FPC model, control and iTg mice have similar body weights, liver weights, blood glucose, hepatic steatosis, and plasma ALT.

“control and iTg mice had similar body weights, liver weights, blood glucose, hepatic steatosis, and plasma ALT (fig. S4, E to H).”

May combine two claims.

Timd4 expression falls after 8 weeks of HF-CDAA feeding, at the same time as impaired liver macrophage efferocytosis appears.

“We observed a decrease in Timd4 expression after 8 weeks of HF-CDAA feeding (fig. S1D), which coincides with the point at which impaired liver macrophage efferocytosis occurs in the HF-CDAA model (see Fig. 1B).”

The quote only partly states this claim.

KC-TIM4-KD in HF-CDAA-fed mice increases liver fibrosis.

“The KD mice had increased liver fibrosis based on picrosirius red and COL1A1 staining (Fig. 3, C and D)”

May combine two claims.

KC-TIM4-KD also lowers efferocytosis and fibrosis in HF-CDAA-fed female mice without affecting hepatosteatosis.

“KC-TIM4-KD also lowered efferocytosis and fibrosis in HF-CDAA–fed female mice without affecting hepatosteatosis (Fig. 3, I to K, and fig. S3, A to E).”

May combine two claims.

In HF-CDAA-fed mice, the ratio of macrophage-associated to free cl-caspase3+ cells falls at 8 and 12 weeks, with more cl-caspase3+ cells.

“the ratio of macrophage-associated:free cl-caspase3+ (apoptotic) cells, which is a measure of efferocytosis by liver macrophages, was markedly decreased at the 8- and 12-week time points, accompanied by an increase in cl-caspase3+ cells (Fig. 1B).”

May combine two claims.

In HF-CDAA-fed mice, anti-TIM4 does not change hepatosteatosis, plasma ALT, or liver Adgre1 mRNA.

“anti-TIM4 did not affect hepatosteatosis, plasma alanine aminotransferase (ALT) activity, or liver macrophage as assessed by Adgre1 mRNA (fig. S2, B to D).”

• AssumptionRests on an assumption: The anti-TIM4 antibody used specifically neutralizes TIM4 without off-target effects.

May combine two claims.

Timd4 mRNA and TIM4 protein are lower in livers of mice with FPC- or HF-CDAA-induced MASH.

“the mRNA encoding the efferocytosis receptor TIM4 (Timd4) and TIM4 protein were decreased in the livers of both FPC- and HF-CDAA–induced MASH mice (fig. S1B, fourth group, and fig. S1, D to I).”

May combine two claims.

Restoring macrophage TIM4 in the FPC model improves efferocytosis and decreases liver fibrosis, HSC activation markers, CK19+ areas, and hCLS.

“Restoration of macrophage TIM4 led to improvements in liver macrophage efferocytosis (Fig. 4L) and decreases in liver fibrosis (Fig. 4M and fig. S4I), α-SMA+ (Fig. 4N) and OPN+ areas (fig. S4J), mRNAs associated with HSC activation [Col1a1, Col1a2, Col1a3, transforming growth factor–β1 (Tgfb1), and Timp1] (Fig. 4O), CK19+ areas (fig. S4K), and hCLS (fig. S4L).”

May combine two claims.

In MASH liver, mRNAs for Mertk, Bai1, and Axl are higher than in control liver.

“The mRNAs encoding c-mer proto-oncogene tyrosine kinase (Mertk), brain-specific angiogenesis inhibitor 1 (Bai1), and AXL receptor tyrosine kinase (Axl) were increased, not decreased, in MASH versus control liver (fig. S1B, first three groups)”

May combine two claims.

After 12 weeks of HF-CDAA feeding, liver TIM4 protein and TIM4 in Clec4f+ KCs are reduced.

“both liver TIM4 protein by immunoblot and TIM4 expression in Clec4f+ KCs by immunofluorescence microscopy were decreased after 12 weeks of HF-CDAA feeding (fig. S1, E and F).”

May combine two claims.

KC-TIM4-KD mice show markedly reduced TIM4 in liver macrophages, with unchanged Clec4f.

“immunofluorescence analysis showed markedly decreased TIM4 expression in liver macrophages in the KD cohort (fig. S2G), whereas the expression of Clec4f was similar in control and KD livers (fig. S2H).”

May combine two claims.

The protective effects of Timd4 macrophages were not accompanied by changes in body weight, liver weight, plasma ALT, or hepatic steatosis.

“The protective effects of Timd4 macrophages were not associated with changes in body weight, liver weight, plasma ALT, or hepatic steatosis (fig. S5, E to G).”

May combine two claims.

IL-10 expression was higher in livers, but not plasma, of TIM4 macrophage-treated HF-CDAA mice.

“Similarly, IL-10 expression was increased in the livers, but not plasma, of TIM4 macrophage–treated HF-CDAA mice (fig. S7, E to G).”

May combine two claims.

The adverse effects of anti-IL-10R were not accompanied by changes in body weight, liver weight, blood glucose, plasma ALT, or hepatic steatosis.

“The detrimental effects of anti-IL-10R were not associated with changes in body weight, liver weight, blood glucose, plasma ALT, or hepatic steatosis (fig. S7, H to K).”

May combine two claims.

Conditioned medium from early MASH macrophages further activated HSCs, shown by increased Spp1 and Timp1 mRNAs, but the increase was smaller when the CM came from macrophages incubated with apoptotic hepatocytes.

“The CM of early MASH macrophages further activated the HSCs, as indicated by an increase in Spp1 and Timp1 mRNAs, but the increase was lower when the CM came from macrophages incubated with apoptotic hepatocytes (Fig. 6C, bars 1 to 3 in each graph).”

May combine two claims.

In the IgG arm, TIM4-iTg mice showed lower Sirius red staining, COL1A1 area, α-SMA area, OPN area, and F4/80+ crown-like structures than control mice.

“the livers of iTg versus control mice in the IgG arm showed decreases in Sirius red staining; percent area of COL1A1, α-SMA, and OPN; and F4/80+ crown-like structures (Fig. 6, G to K, third versus first bars).”

May combine two claims.

CM from WT macrophages exposed to apoptotic hepatocytes lowered HSC expression of Spp1 and Timp1, but this effect was absent with CM from TIM4-KD macrophages exposed to apoptotic hepatocytes.

“As before, the CM of WT macrophages exposed to apoptotic hepatocytes lowered HSC expression of Spp1 and Timp1, but this effect was not observed with CM from TIM4-KD macrophages exposed to apoptotic hepatocytes (Fig. 6E).”

May combine two claims.

In primary mouse HSCs partially activated by low TGF-β1, recombinant IL-10 lowered Col3a1 and Acta2 expression, and anti-IL-10R prevented this effect.

“IL-10 lowered the expression of Col3a1 and actin alpha 2, smooth muscle (Acta2) in the HSCs, which was prevented by anti–IL-10R (fig. S7A)”

• AssumptionRests on an assumption: The anti–IL-10R antibody used specifically blocks IL-10 receptor signaling in the ex vivo and in vivo experiments.

May combine two claims.

All measured fibrosis parameters were higher in TIM4-iTg mice given anti-IL-10R than in those given IgG, abolishing the fibrosis-lowering effect of increased macrophage TIM4.

“However, all of these parameters were higher in iTg mice treated with anti–IL-10R versus IgG, negating the liver fibrosis–mitigating effect of boosting macrophage TIM4 expression (Fig. 6, G to K, fourth versus third bars).”

• AssumptionRests on an assumption: The anti–IL-10R antibody used specifically blocks IL-10 receptor signaling in the ex vivo and in vivo experiments.

May combine two claims.

TIMD4 HMDM treatment did not change body weight, liver weight, or hepatic steatosis.

“without changes in body weight, liver weight, and hepatic steatosis (fig. S6, F and G).”

May combine two claims.

The study's results uncover a mechanism in the shift from fatty liver to early MASH fibrosis and point to a targeted treatment approach for halting fibrotic MASH.

“These findings reveal a key process in the progression from hepatic steatosis to early MASH fibrosis and identify a mechanism-based therapeutic strategy to prevent fibrotic MASH progression.”

May combine two claims.

Mouse and human MASH show impaired efferocytosis together with reduced TIM4 on liver macrophages.

“In summary, mouse and human MASH show evidence of impaired efferocytosis, and this is associated with a decrease in TIM4 expression on liver macrophages.”

May combine two claims.

Defective clearance of both necroptotic and apoptotic hepatocytes, caused by distinct mechanisms, both contribute to liver fibrosis in steatohepatitis/MASH.

“We therefore conclude that defective clearance of both necroptotic and apoptotic hepatocytes, which is caused by distinct mechanisms, both contribute to liver fibrosis in steatohepatitis/MASH.”

May combine two claims.

Changes in TIM4-mediated efferocytosis in the models were directly and mechanistically linked to liver fibrosis, with more fibrosis after macrophage TIM4 knockdown and the opposite after TIM4 restoration.

“We showed that the changes in TIM4-mediated efferocytosis in our various models were directly and mechanistically linked to liver fibrosis, that is, increased fibrosis with macrophage TIM4 KD and vice versa for macrophage TIM4”

Probably not a substantial claim: may not pass S3 (load-bearing).

In mice exposed to carbon tetrachloride or acetaminophen, STAT3-IL-10-IL-6-induced reprogramming of efferocytosing macrophages contributed to liver repair.

“Moreover, in mice exposed to carbon tetrachloride or acetaminophen, signal transducer and activator of transcription 3–IL-10–IL-6–induced reprogramming of efferocytosing macrophages contributed to liver repair (44).”

• cites [44] sourceNot checked — no full text of the source

May combine two claims.

Restoring macrophage TIM4 by in vivo transgenesis or by cell therapy with TIM4-expressing macrophages improves efferocytosis and slows progression to liver fibrosis.

“These combined data show that restoration of macrophage TIM4 using in vivo transgenesis or cell therapy with TIM4-expressing macrophages improves efferocytosis and dampens the progression to liver fibrosis.”

May combine two claims.

Genetic correction of impaired TIM4-mediated efferocytosis can lower liver fibrosis through efferocytosis-induced macrophage reprogramming to secrete IL-10, which decreases HSC activation.

“and that genetic correction of this impairment can lower liver fibrosis through the efferocytosis-induced reprogramming of macrophages to secrete IL-10, which decreases HSC activation (fig. S7L).”

May combine two claims.

The pan-caspase inhibitor emricasan failed to improve liver histology and increased liver fibrosis in MASH patients.

“the pan-caspase inhibitor emricasan failed to improve liver histology and paradoxically increased liver fibrosis in patients with MASH (11).”

• cites [11] sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

TREM2-mediated efferocytosis by liver macrophages can promote repair of liver injury.

“TREM2-mediated efferocytosis by liver macrophages can promote the repair of liver injury (20).”

• cites [20] sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

All mouse experiments were approved by the Columbia University Institutional Animal Care and Use Committee.

“All mouse experiments were approved by the Columbia University Institutional Animal Care and Use Committee (protocol no. AABL5573).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Uptake of apoptotic hepatocytes by IL-4-treated BMDMs in vitro promotes an immune-suppressive phenotype.

“a previous study showed that the uptake of apoptotic hepatocytes by IL-4–treated BMDMs in vitro promotes an immune-suppressive phenotype (45)”

• cites [45] sourceNot checked — no full text of the source

Classified as probably not a substantial claim. May combine two claims.

The study attempted to mitigate the limitation of model fidelity by using complementary mouse models sharing features with human MASH and by looking for key aspects in human MASH liver and primary human liver cells.

“We attempted to mitigate this limitation by using complementary mouse models, each of which shares features with human MASH, and by looking for key aspects of our discoveries in human MASH liver and primary liver cells from human liver.”

May combine two claims.

Genetic restoration of TIM4 in macrophages in MASH or treatment of MASH mice with macrophages engineered to express TIM4 improves clearance of apoptotic hepatocytes and decreases liver fibrosis.

“Accordingly, genetic restoration of TIM4 in macrophages in MASH or treatment of MASH mice with macrophages genetically engineered to express TIM4 improves the clearance of apoptotic hepatocytes and decreases liver fibrosis.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The data were analyzed in an unblinded manner.

“The data were analyzed in an unblinded manner.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Ex vivo experiments were repeated with at least three biological replicates.

“The ex vivo experiments were repeated with at least three biological replicates”

Probably not a substantial claim: may not pass S3 (load-bearing).

Human studies were approved by the Columbia University Institutional Review Board.

“Human studies were approved by Columbia University Institutional Review Board (protocol no. IRB-AAAU1906).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Mouse data exclusion criteria were more than 20% body weight loss during diet feeding or a liver weight to body weight ratio below 6% after MASH diet feeding.

“Data exclusion criteria in the mouse experiments were >20% loss of body weight during the diet feeding period or a ratio of liver weight to body weight of <6% after MASH diet feeding.”

Probably not a substantial claim: may not pass S3 (load-bearing).

All mice were randomly assigned to experimental groups by investigators blinded to group assignment.

“All of the mice were randomly assigned to experimental groups by investigators who were blinded in terms of group assignment.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Impaired efferocytosis may also lead to additional profibrotic processes, such as HSC activation by uncleared dead hepatocytes.

“impaired efferocytosis may also lead to additional profibrotic processes, such as HSC activation by uncleared dead hepatocytes.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In vivo experiments used more than seven mice per group and two complementary diet-induced MASH/steatohepatitis models.

“and the in vivo experiments used n > 7 mice per group and two complementary diet–induced MASH/steatohepatitis models.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The sample size for mouse experiments was determined by previous mouse MASH or pilot experiments.

“The sample size for the mouse experiments was determined by previous mouse MASH or pilot experiments.”

May combine two claims.

The macrophage reprogramming process has distinct features in MASH, consistent with the finding that restoring TIM4-mediated efferocytosis in MASH decreased liver Tgfb1.

“Thus, we propose that this reprogramming process has some distinct features in the unique setting of MASH, which is consistent with our showing that restoration of TIM4-mediated efferocytosis in MASH decreased liver Tgfb1.”

May combine two claims.

Decreased TIM4 expression in liver macrophages during MASH progression contributes to defective efferocytosis, leading to impaired macrophage IL-10 production and increased HSC activation and liver fibrosis.

“In summary, we have shown that decreased expression of TIM4 in liver macrophages during MASH progression contributes to defective efferocytosis, leading to impaired macrophage IL-10 production and increased HSC activation and liver fibrosis.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Animal protocol AABL5573 was approved by the Institutional Animal Care and Use Committee at Columbia University.

“Animal protocol AABL5573 for these studies was approved by the Institutional Animal Care and Use Committee at Columbia University.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Experimental MASH models may not reflect human MASH in mechanisms and treatment strategies.

“experimental MASH models may not reflect human MASH both in terms of mechanisms and treatment strategies.”